Phosphonium-ion tethered tetracycline drugs for treatment of cancer

ABSTRACT

This invention relates to compounds that are useful as cancer therapies. The compounds comprise derivatives of tetracycline antibiotics, e.g. doxycycline, having a phosphonium cation tethered to the tetracycline tetracycle. The invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds.

This invention relates to compounds that disrupt cell function, such asthe disruption of cell metabolism in particular cancer cell metabolism,that are useful as cancer therapies. The compounds comprise derivativesof tetracycline antibiotics, e.g. doxycycline, having a phosphoniumcation tethered to the tetracycline tetracycle. The invention alsorelates to methods of using said compounds and to pharmaceuticalformulations comprising said compounds.

BACKGROUND

Cancer is the fourth greatest cause of mortality in the developed world.In 2016 it was predicted that more than 1.6 million new cases of cancerwould be diagnosed in the U.S. alone, and that cancer would beresponsible for nearly 600,000 U.S. deaths.

Cancer is characterized by the unregulated proliferation of cells, whichdisrupt the function of tissues. The proliferation of cells can becaused by an abnormal increase in cell production or a disruption in thecell death pathway. In any event, disruptors of cell function can impactthe proliferation of cells and, in particular, cancer cells by reducingor inhibiting cell proliferation. For example, the modulation of cancercell metabolism can lead to the reduction or inhibition of cellproliferation. Equally, the compounds of the invention may reduce,disrupt, or inhibit the growth or proliferation of a cancer cell or itmay induce the death of a cancer cell. As such, cancer cell metabolism,and reducing cell proliferation, is a potential target for disruptingcancer growth and ultimately a therapeutic pathway for cancer treatment.Accordingly, the certain embodiments of the invention contemplatecompounds that modulate cancer cell metabolism and/or reduce cellproliferation. Reduction in cell proliferation could be achieved eitherby increasing cell death or by reducing the rate of cell growth.

It has been observed that certain compounds having antibiotic activityhave a beneficial effect when administered to patients with cancer. Theinventors have found that compounds having a phosphonium ion linked to atetracycline antibiotic are able to modulate cancer cell metabolism incancer cell lines and, accordingly, prevent and/or treat cancer.

The “prevention” of cancer may be taken as including the prevention ofthe formation of tumours, including primary tumours, metastatic tumours,or tumours associated with cancer onset, resistance or relapse. Theprevention of cancer may also be taken as encompassing the prevention ofthe progression of cancer. In this context, prevention of development ofcancer may be demonstrated by preventing an increase in the “stage” of atumour (using an appropriate cancer staging method) that has beentreated using the compounds of the invention. The prevention of increasein cancer stage may be compared to progression of an untreated tumour,or compared to the extent of progression that would be expected by aclinician in the event that the tumour was not treated.

The “treatment” of cancer may be taken as including any improvement ofpathology, symptoms or prognosis that is achieved in respect of cancerin a subject receiving compounds of the invention. Treatment may beindicated by a partial improvement of such indications, or by a totalimprovement (e.g. the absence of cancer following medical use of thecompounds of the invention).

Accordingly, the prevention and/or treatment as defined above areintended aims of certain embodiments of the invention. The abovedefinitions of treatment or prevention of cancer apply equally to thespecific forms of cancer that are also contemplated.

Recent developments in cancer therapy have suggested that certainantibiotic compounds may be useful in cancer treatment. The mechanismsby which these agents, which include the antibiotics azithromycin anddoxycycline, exert a therapeutic effect have been open to markedlydifferent explanations. Some authors have suggested that these agentsinhibit matrix metalloproteinases (MMPs) and thereby achieve ananti-inflammatory effect, while others suggest that they impair thecells' response to DNA damage, thereby increasing the effectiveness ofchemotherapy or radiotherapy on bulk tumour cells. Still other articleshave indicated that the antibiotics target mitochondrial function.

However, there have also been reports that antibiotic use can increasethe risk of colorectal cancer. A recent study identified that increasingduration of antibiotic use was significantly associated with anincreased risk of colorectal adenoma (Cao Y, Wu K, Mehta R, et al,“Long-term use of antibiotics and risk of colorectal adenoma”, Gut,2017, 0, page 1-7).

Surprisingly, the inventors have found that the compounds having aphosphonium ion linked to a tetracycline antibiotic have increasedactivity against certain cancer cell lines compared to the correspondingantibiotic, e.g. doxycycline. This is demonstrated by the reduced cancercell proliferation observed in a cell confluence assay.

Also provided is a method of preventing and/or treating cancer in asubject needing such prevention and/or treatment, the method comprisingadministering a therapeutically effective amount of a compound of theinvention to the subject. A therapeutically effective amount of acompound of the invention may be an amount of such a compound sufficientto treat a variety of cancers, including the modulation of cancer cellsor other dysfunctional cells (such as tumour initiating cells, stem-likecancer cells, cancer stem cells, or a population of cells with stemcell-like features that exist in tumors and that give rise to the bulkof tumor cells with more differentiated phenotypes). References tocancer cells include hybrid cells and giant cells. It will beappreciated that the therapeutically effective amount of the compound ofthe invention may be provided in a single incidence of administration,or cumulatively through multiple incidences of administration.

The same considerations regarding the types of cancers to be treated,and benefits provided by treatment, described with respect to themedical uses of the compounds of the invention also apply to the methodsof treatment of the invention.

BRIEF SUMMARY OF THE DISCLOSURE

In a first aspect of the invention there is provided a compoundcomprising an ion of formula (I) or a pharmaceutically acceptable saltthereof:

wherein

-   R^(W) is H or OH;-   R^(X) is H or OH;-   R^(Y) is H, C₁-C₆-alkyl or C₁-C₆-haloalkyl;-   R^(Z) is H, NR^(Z1)R^(Z2), C₁-C₆-haloalkyl, or halo, wherein R^(Z1)    and R^(Z2) are both independently selected from H or C₁-C₆-alkyl;-   -L¹- is absent or is —CR^(2a)R^(2b)—;-   -L²- is absent or is independently selected from —O—, —S—,    —NR^(3a)—, —C(O)NR^(3b)—, —C(O)—, —OC(O)—, —NR^(3b)C(O)—, NR⁵S(O)₂—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O— and —NR^(3b)C(O)NR^(3b);-   -L³- and -L⁵- are each independently at each occurrence selected    from —C₁-C₄-alkylene-, each alkylene group being unsubstituted or    substituted with from 1 to 10 independently selected R⁴ groups;    provided that any -L³- or -L⁵- group that is attached at each end to    an atom selected from oxygen, nitrogen, sulphur or phosphorous is    —C₂-C₄-alkylene-;-   -L⁴- is independently at each occurrence either absent or is    selected from: —O—, —S—, —NR^(3a)—, —C(O)—, —OC(O)—, —C(O)O—, —SO₂—,    —S(O)—, —NR^(3b)C(O)—, —C(O)NR^(3b), NR^(3b)S(O)₂—, —S(O)₂NR^(3b)—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O—, NR^(3b)C(O)NR^(3b), —CR⁵═CR⁵— and    —C≡C—;-   n is an integer selected from 0, 1, 2, 3, 4 and 5;-   wherein L¹, L², L³ L⁴ and L⁵ together form a linker and L¹, L², L³    L⁴ and L⁵ are selected such that length of the linker is from 3 to    16 atoms;-   R^(1a), R^(1b) and R^(1c) are each independently selected from    phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃    to C₈-cycloalkyl, C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl;    wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered    heteroaryl is optionally substituted with from 1 to 5 independently    selected R^(1d) groups; and-   wherein said C₃ to C₈-cycloalkyl, C₁-C₈-alkyl and 4- to 8-membered    heterocycloalkyl is optionally substituted with from 1 to 5    independently selected R^(1e) groups; provided that R^(1a), R^(1b)    and R^(1c) are not each unsubstituted phenyl; wherein R^(1a) and    R^(1b) are optionally connected to each other via a bond or a group    selected from —O—, NR^(6a), and C₁-C₃-alkylene;-   R^(1d) is independently at each occurrence selected from:    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷,    halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷, NR⁷C(O)OR⁷,    OC(O)NR⁷R⁷ and S(O)₂NR⁷R⁷;-   R^(1e) is independently at each occurrence selected from: oxo,    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷,    halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷, S(O)₂NR⁷R⁷,    OC(O)NR⁷R⁷ and NR⁷C(O)OR⁷;-   R^(2a) and R^(2b) are each independently selected from H and    C₁-C₄-alkyl;-   R^(3a) is independently at each occurrence selected from H,    C₁-C₆-alkyl, —C(O)-C₁-C₆-alkyl and —S(O)₂-C₁-C₆-alkyl;-   R^(3b) is each independently at each occurrence selected from H and    C₁-C₆-alkyl;-   R⁴ is independently at each occurrence selected from: C₁-C₆-alkyl,    C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸,    C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷,    S(O)₂R⁷, NR⁷C(O)OR⁷, OC(O)NR⁷R⁷ and S(O)₂NR⁷R⁷;-   R⁵ is independently at each occurrence selected from H, C₁-C₄-alkyl    and halo;-   R⁶ is independently at each occurrence selected from: H, C₁-C₆-alkyl    and C₁-C₆-haloalkyl;-   R⁷ and R^(6a) are each independently at each occurrence selected    from: H and C₁-C₆-alkyl;-   R⁸ is independently at each occurrence selected from: H,    C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl;-   and wherein any of the abovementioned alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is    optionally substituted where chemically allowable by from 1 to 4    groups independently selected from oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR^(a), NR^(a)R^(b), SR^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), halo, cyano, nitro, C(O)R^(a),    S(O)₂OR^(a), S(O)₂R^(a), S(O)R^(a) and S(O)₂NR^(a)R^(a); wherein    R^(a) is independently at each occurrence selected from: H and    C₁-C₆-alkyl; and R^(b) is independently at each occurrence selected    from: H, C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl.

A compound comprising an ion of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein

-   R^(W) is H or OH;-   R^(X) is H or OH;-   R^(Y) is H, C₁-C₆-alkyl or C₁-C₆-haloalkyl;-   R^(Z) is H, NR^(Z1)R^(Z2), C₁-C₆-haloalkyl, or halo, wherein R^(Z1)    and R^(Z2) are both independently selected from H or C₁-C₆-alkyl;-   -L¹- is absent or is —CR^(2a)R^(2b)-;-   -L²- is absent or is independently selected from —O—, —S—,    —NR^(3a)-, —C(O)NR^(3b)-, —C(O)—, —OC(O)—, —NR^(3b)C(O)—, NR⁵S(O)₂—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O— and —NR^(3b)C(O)NR^(3b);-   -L³- and -L⁵- are each independently at each occurrence selected    from —C₁-C₄-alkylene-, each alkylene group being unsubstituted or    substituted with from 1 to 10 independently selected R⁴ groups;    provided that any -L³- or -L⁵- group that is attached at each end to    an atom selected from oxygen, nitrogen, sulphur or phosphorous is    —C₂-C₄-alkylene-;-   -L⁴- is independently at each occurrence either absent or is    selected from: —O—, —S—, —NR^(3a)—, —C(O)—, —OC(O)—, —C(O)O—, —SO₂—,    —S(O)—, —NR^(3b)C(O)—, —C(O)NR^(3b), NR^(3b)S(O)₂—, —S(O)₂NR^(3b)—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O—, NR^(3b)C(O)NR^(3b), —CR⁵═CR⁵— and    —C═C—;-   n is an integer selected from 0, 1, 2, 3, 4 and 5;-   wherein L¹, L², L³ L⁴ and L⁵ together form a linker and L¹, L², L³    L⁴ and L⁵ are selected such that length of the linker is from 3 to    16 atoms;-   R^(1a), R^(1b) and R^(1c) are each independently selected from    phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃    to C₈-cycloalkyl, C₁-C₈-alkyl and 5- to 8-membered heterocycloalkyl;    wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered    heteroaryl is optionally substituted with from 1 to 5 independently    selected R^(1d) groups; and-   wherein said C₃ to C₈-cycloalkyl, C₁-C₈-alkyl and 5- to 8-membered    heterocycloalkyl is optionally substituted with from 1 to 5    independently selected R^(1e) groups; provided that R^(1a), R^(1b)    and R^(1c) are not each unsubstituted phenyl;-   R^(1d) is independently at each occurrence selected from:    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷,    halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷, NR⁷C(O)OR⁷,    OC(O)NR⁷R⁷ and S(O)₂NR⁷R⁷;-   R^(1e) is independently at each occurrence selected from: oxo,    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷,    halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷, S(O)₂NR⁷R⁷,    OC(O)NR⁷R⁷ and NR⁷C(O)OR⁷;-   R^(2a) and R^(2b) are each independently selected from H and    C₁-C₄-alkyl;-   R^(3a) is independently at each occurrence selected from H,    C₁-C₆-alkyl, —C(O)—C₁-C₆-alkyl and —S(O)₂—C₁-C₆-alkyl;-   R^(3b) is each independently at each occurrence selected from H and    C₁-C₆-alkyl;-   R⁴ is independently at each occurrence selected from: C₁-C₆-alkyl,    C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸,    C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷,    S(O)₂R⁷, NR⁷C(O)OR⁷, OC(O)NR⁷R⁷ and S(O)₂NR⁷R⁷;-   R⁵ is independently at each occurrence selected from H, C₁-C₄-alkyl    and halo;-   R⁶ is independently at each occurrence selected from: H, C₁-C₆-alkyl    and C₁-C₆-haloalkyl;-   R⁷ is independently at each occurrence selected from: H and    C₁-C₆-alkyl;-   R⁸ is independently at each occurrence selected from: H,    C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl;-   and wherein any of the abovementioned alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is    optionally substituted where chemically allowable by from 1 to 4    groups independently selected from oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR^(a), NR^(a)R^(b), SR^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), halo, cyano, nitro, C(O)R^(a),    S(O)₂OR^(a), S(O)₂R^(a), S(O)R^(a) and S(O)₂NR^(a)R^(a); wherein    R^(a) is independently at each occurrence selected from: H and    C₁-C₆-alkyl; and R^(b) is independently at each occurrence selected    from: H, C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl.

It may be that R^(X) is H.

For the absence of doubt, where n is greater than 1, each -L⁴-L⁵- unitis selected independently of the other -L⁴-L⁵- unit or -L⁴-L⁵- units.Thus, each -L⁴-L⁵- unit may be the same or they may be different.

For the absence of doubt the atom length of the linkers formed by L¹,L², L³ L⁴ and L⁵ is the number of atoms in a straight chain from thephosphorous atom of the phosphonium to the carbon atom via which thelinker is attached to the tetracycline portion of the cations. Thelength does not include any substituents or branching that might bepresent on the chain.

For the absence of doubt where a bivalent group (e.g. L¹, L², L³, L⁴, L⁵or a combination thereof) is represented in text, the left-hand portionof the linker group is attached, either directly or indirectly, to thecarbon atom via which the linker is attached to the tetracycline portionof the cation and the right hand portion of the linker group isattached, either directly or indirectly, to the phosphorous atom of thephosphonium.

In embodiments the ion of formula (I) may be an ion according to formula(II):

In embodiments the ion of formula (I) may be an ion according to formula(III):

In embodiments the ion of formula (I) may be an ion according to formula(IIa):

In embodiments the ion of formula (I) may be an ion according to formula(IIIa):

In embodiments the ion of formula (I) may be an ion according to formula(IIb):

In embodiments the ion of formula (I) may be an ion according to formula(IIIb):

In an embodiment the ion of formula (I) may be an ion according toformula (IV):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In an embodiment the ion of formula (I) may be an ion according toformula (V):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments the ion of formula (I) may be an ion according to formula(IVa):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments the ion of formula (I) may be an ion according to formula(IVb):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments the ion of formula (I) may be an ion according to formula(Va):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments the ion of formula (I) may be an ion according to formula(Vb):

wherein o is selected from 3 to 10; p is selected from 1 to 3, whereinR^(4a) and R^(4b) are each independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

The following statements apply to compounds of any of formulae (I) to(Vb). These statements are independent and interchangeable. In otherwords, any of the features described in any one of the followingstatements may (where chemically allowable) be combined with thefeatures described in one or more other statements below. In particular,where a compound is exemplified or illustrated in this specification,any two or more of the statements below which describe a feature of thatcompound, expressed at any level of generality, may be combined so as torepresent subject matter which is contemplated as forming part of thedisclosure of this invention in this specification.

In embodiments R^(Z) is H, NMe₂, CF₃, Cl or F. In embodiments R^(Z) isH. In embodiments R^(Z) is NMe₂,

In embodiments R^(X) is H. In embodiments R^(X) is OH.

In embodiments R^(Y) is H or C₁-C₆ alkyl, e.g. CH₃ In embodiments R^(Y)is C₁-C₆ alkyl, e.g. CH₃.

In embodiments R^(W) is H. In embodiments R^(W) is OH.

In embodiments R^(Z) is H, NMe₂, CF₃, Cl or F; R^(X) is H or OH, R^(Y)is H or CH₃, and R^(W) is H or OH. In embodiments R^(Z) is H, NMe₂, CF₃,Cl or F; R^(X) is H, R^(Y) is H or CH₃, and R^(W) is H or OH.

Where R^(Z) is not H, it is preferably positioned para to the OH groupdepicted in formula (I).

In embodiments R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W) is OH.Accordingly, the tetracyclic core of formula (I) is equivalent todoxycycline. In embodiments R^(Z) is H, R^(X) is OH, R^(Y) is CH₃, andR^(W) is H. Accordingly, the tetracyclic core of formula (I) isequivalent to tetracycline. In embodiments R^(Z) is NMe₂, R^(X) is H,R^(Y) is H, and R^(W) is H. Accordingly, the tetracyclic core of formula(I) is equivalent to minocycline. In embodiments R^(Z) is Cl, R^(X) isOH, R^(Y) is CH₃, and R^(W) is H. Accordingly, the tetracyclic core offormula (I) is equivalent to chlorotetracycline. In embodiments R^(Z) isH, R^(X) is OH, R^(Y) is CH₃, and R^(W) is OH. Accordingly, thetetracyclic core of formula (I) is equivalent to oxytetracycline.

It may be that the tetracyclic core of the compound of formula (I) isnot tetracycline or oxytetracycline.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, 5- or 6-membered heteroaryl and C₃ toC₈-cycloalkyl, wherein said phenyl, biphenyl and 5- or 6-memberedheteroaryl is optionally substituted with from 1 to 5 independentlyselected R^(1d) groups, and wherein said C₃ to C₈-cycloalkyl isoptionally substituted with from 1 to 5 independently selected R^(1e)groups; provided that R^(1a), R^(1b) and R^(1c) are not eachunsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein saidphenyl, biphenyl and pyridyl is optionally substituted with from 1 to 5independently selected R^(1d) groups, and wherein said cyclohexyl groupis optionally substituted with from 1 to 5 independently selected R^(1e)groups; provided that R^(1a), R^(1b) and R^(1c) are not eachunsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein saidphenyl, biphenyl and pyridyl is optionally substituted with 1 to 3independently selected R^(1d) groups, and wherein said cyclohexyl groupis optionally substituted with 1 to 3 independently selected R^(1e)groups; provided that R^(1a), R^(1b) and R^(1c) are not eachunsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-memberedheteroaryl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or10-membered heteroaryl is optionally substituted with from 1 to 5independently selected R^(1d) groups, provided that R^(1a), R^(1b) andR^(1c) are not each unsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, optionally substituted with from 1 to 5independently selected R^(1d) groups, provided that R^(1a), R^(1b) andR^(1c) are not each unsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl; wherein said phenyl is optionally substituted withfrom 1, 2 or 3 independently selected R^(1d) groups, provided thatR^(1a), R^(1b) and R^(1c) are not each unsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl; wherein said phenyl is optionally substituted withfrom 1, 2 or 3 R^(1d) groups; provided that R^(1a), R^(1b) and R^(1c)are not each unsubstituted phenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from C₃ to C₈ cycloalkyl, C₁-C₈-alkyl and 5- to 8-memberedheterocycloalkyl; wherein said C₃ to C₈ cycloalkyl, C₁-C₈-alkyl and 5-to 8-membered heterocycloalkyl is optionally substituted with from 1 to5 independently selected R^(1e) groups. In embodiments, R^(1a), R^(1b)and R^(1c) are each independently selected from C₃ to C₈ cycloalkyl,C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl; wherein said C₃ to C₈cycloalkyl, C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl isoptionally substituted with from 1 to 5 independently selected R^(1e)groups.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from C₃ to C₈ cycloalkyl, C₁-C₈-alkyl and 5- to 8-memberedheterocycloalkyl; wherein said C₃ to C₈ cycloalkyl, C₁-C₈-alkyl and 5-to 8-membered heterocycloalkyl is optionally substituted with from 1 to5 independently selected R^(1e) groups.

In embodiments R^(1a), R^(1b) and R^(1c) are different or the same.

In embodiments, R^(1e) is independently at each occurrence selected fromC₁-C₆-alkyl, halo, OR⁶, NR⁷R⁸ and S(O)₂OR⁷.

In embodiments, R^(1e) is independently at each occurrence selected fromOCH₃, OCH₂(CH₃)₂, N(CH₃)₂, SO₂OH, F and Cl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein saidphenyl, biphenyl and pyridyl is optionally substituted with 1 to 3independently selected R^(1d) groups, wherein R^(1d) is independently ateach occurrence selected from C₁-C₆-alkyl, halo, OR⁶, NR⁷R⁸ andS(O)₂OR⁷.

In embodiments, R^(1a), R^(1b) and R^(1c) are each independentlyselected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein saidphenyl, biphenyl and pyridyl is optionally substituted with 1 to 3independently selected R^(1d) groups, wherein R^(1d) is independently ateach occurrence selected from OCH₃, OCH₂(CH₃)₂, N(CH₃)₂, SO₂OH, F andCl.

In embodiments, R^(1a) is C₃ to C₈-cycloalkyl, R^(1b) is C₃ toC₈-cycloalkyl and R^(1c) is C₃ to C₈-cycloalkyl.

In embodiments, R^(1a) and R^(1b) are each unsubstituted phenyl andR^(1c) is independently selected from: substituted phenyl, biphenyl,naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃ to C₈-cycloalkyl,C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl.

In embodiments, R^(1a) and R^(1b) are each unsubstituted phenyl andR^(1c) is independently selected from: substituted phenyl, biphenyl,naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃ to C₈-cycloalkyl,C₁-C₈-alkyl and 5- to 8-membered heterocycloalkyl.

In embodiments, R^(1a) and R^(1b) are each unsubstituted phenyl andR^(1c) is substituted phenyl.

In embodiments, R^(1a) and R^(1b) are each unsubstituted phenyl andR^(1c) is pyridyl.

In embodiments, R^(1a) and R^(1b) are each C₃ to C₈-cycloalkyl andR^(1c) is independently selected from: phenyl, biphenyl, naphthyl, 5-,6-, 9- or 10-membered heteroaryl, C₁-C₈-alkyl and 4- to 8-memberedheterocycloalkyl.

In embodiments, R^(1a) and R^(1b) are each C₃ to C₈-cycloalkyl andR^(1c) is independently selected from: phenyl, biphenyl, naphthyl, 5-,6-, 9- or 10-membered heteroaryl, C₁-C₈-alkyl and 5- to 8-memberedheterocycloalkyl.

In embodiments, R^(1a) and R^(1b) are each cyclohexyl and R^(1c) issubstituted biphenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each substituted phenyl.It may be that R^(1a), R^(1b) and R^(1c) are each fluorophenyl, e.g.para-fluorophenyl. It may be that R^(1a), R^(1b) and R^(1c) are eachchlorophenyl, e.g. para-chlorophenyl. It may be that R^(1a), R^(1b) andR^(1c) are each methoxyphenyl, e.g. para-methoxyphenyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each C₃ to C₈-cycloalkyl.In embodiments, R^(1a), R^(1b) and R^(1c) are each cyclohexyl.

In embodiments, R^(1a), R^(1b) and R^(1c) are each benzyl.

In embodiments, at least one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9-or 10-membered heteroaryl or 4- to 8-membered heterocycloalkyl. It maybe that a single one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9- or10-membered heteroaryl or 4- to 8-membered heterocycloalkyl. Inembodiments, at least one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9- or10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, whereinsaid heteroaryl or heterocycloalkyl group comprises at least onenitrogen atom in the ring. It may be that a single one of R^(1a), R^(1b)and R^(1c) is 5-, 6-, 9- or 10-membered heteroaryl or 4- to 8-memberedheterocycloalkyl, wherein said heteroaryl or heterocycloalkyl groupcomprises at least one nitrogen atom in the ring. In embodiments, atleast one of R^(1a), R^(1b) and R^(1c) is 5- or 6-membered heteroarylgroup, wherein said heteroaryl group comprises at least one nitrogenatom in the ring. It may be that a single one of R^(1a), R^(1b) andR^(1c) is 5- or 6-membered heteroaryl group, wherein said heteroarylgroup comprises at least one nitrogen atom in the ring. In theseembodiments, it may be that any of R^(1a), R^(1b) and R^(1c) that arenot heteroaryl or heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.

In embodiments, at least one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9-or 10-membered heteroaryl or 5- to 8-membered heterocycloalkyl. It maybe that a single one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9- or10-membered heteroaryl or 5- to 8-membered heterocycloalkyl. Inembodiments, at least one of R^(1a), R^(1b) and R^(1c) is 5-, 6-, 9- or10-membered heteroaryl or 4- to 8-membered heterocycloalkyl, whereinsaid heteroaryl or heterocycloalkyl group comprises at least onenitrogen atom in the ring. It may be that a single one of R^(1a), R^(1b)and R^(1c) is 5-, 6-, 9- or 10-membered heteroaryl or 5- to 8-memberedheterocycloalkyl, wherein said heteroaryl or heterocycloalkyl groupcomprises at least one nitrogen atom in the ring. In embodiments, atleast one of R^(1a), R^(1b) and R^(1c) is 5- or 6-membered heteroarylgroup, wherein said heteroaryl group comprises at least one nitrogenatom in the ring. It may be that a single one of R^(1a), R^(1b) andR^(1c) is 5- or 6-membered heteroaryl group, wherein said heteroarylgroup comprises at least one nitrogen atom in the ring. In theseembodiments, it may be that any of R^(1a), R^(1b) and R^(1c) that arenot heteroaryl or heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.

In embodiments, at least one of R^(1a), R^(1b) and R^(1c) is C₁-C₆-alkyl(e.g. methyl). It may be that a single one of R^(1a), R^(1b) and R^(1c)is C₁-C₆-alkyl (e.g. methyl). It may be that two or more of R^(1a),R^(1b) and R^(1c) is C₁-C₆-alkyl (e.g. methyl). It may be that each ofR^(1a), R^(1b) and R^(1c) is C₁-C₆-alkyl (e.g. methyl). In theseembodiments, it may be that any of R^(1a), R^(1b) and R^(1c) that arenot C₁-C₆-alkyl are phenyl, e.g. unsubstituted phenyl.

It may be that R^(1a) and R^(1b) are connected to each other via a bondor a group selected from —O—, NR^(6a), and C₁-C₃-alkylene. It may bethat R^(1a) and R^(1b) are connected to each other via a bond or aC₁-C₃-alkylene group. It may be that R^(1a) and R^(1b) are connected toeach other via a bond. It may be that R^(1a) and R^(1b) are each phenyland are connected to each other via a bond or a group selected from —O—,NR^(6a), and C₁-C₃-alkylene. It may be that R^(1a) and R^(1b) are eachphenyl and are connected to each other via a bond or a C₁-C₃-alkylenegroup. It may be that R^(1a) and R^(1b) are each phenyl and areconnected to each other via a bond.

It may be that R^(1a) and R^(1b) are not connected to each other via abond or a group selected from —O—, NR^(6a), and C₁-C₃-alkylene.

In embodiments, —⁺PR^(1a)R^(1b)R^(1c) is selected from:

In embodiments R^(2a) and R^(2b) are each independently selected from Hand methyl.

In embodiments, L¹ is absent.

In embodiments, L¹ is CR^(2a)R^(2b), e.g. —CH₂—.

In embodiments, L¹ is absent or —CH₂—.

In embodiments, L² is —NR^(3a), —C(O)—, —C(O)NR^(3b)— or —NR^(3b)C(O)—.Preferably, L² is —C(O)NR^(3b)— or —NR^(3b)C(O)—. In embodiments R^(3a)and R^(3b) are each independently at each occurrence selected from H andmethyl. In embodiments R^(3b) is H. Accordingly, in embodiments L² maybe —C(O)NR^(3b)—, for example C(O)NH—.

In embodiments -L²-L¹- represents —C(O)NR^(3b)—, e.g. —C(O)NH—.

In embodiments -L²-L¹- represents —C(O)NR^(3b)CR^(2a)R^(2b)—, e.g.—C(O)NHCH₂—.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (II) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (III) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (Ila) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IIIa) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, andR^(W) is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IIb) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IIIb) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, andR^(W) is OH.

In embodiments, -(L⁵-L⁴-)_(n)-L³- is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)-,—(CR^(4a)R^(4b))_(j)-L⁴-(CR^(4c)R^(4d))_(k)-,—(CH₂)_(q)-L⁴-[O—(CH₂)_(r)]₁₋₃—(CH₂)_(s)—,—(CH₂)_(q)—[O—(CH₂)_(r)]₁₋₃-L⁴—(CH₂)_(s)—,—(CH₂)_(q)-L⁴-[(CH₂)_(r)—O]₁₋₃—(CH₂)_(s)— or—(CH₂)_(q)—[(CH₂)_(r)—O]₁₋₃-L⁴—(CH₂)_(s)—; wherein o is selected from 3to 10; p is selected from 1 to 3; j is selected from 1 to 3; k is 3 to10; q and s are each independently selected from 0 to 3; and r isselected from 1 to 3.

In embodiments R^(4a) and R^(4b) are each independently at eachoccurrence selected from: H, C₁-C₆-alkynyl, C₂-C₆-alkenyl,C₁-C₆-haloalkyl, OR⁶, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁸, halo, cyano, nitro,C(O)R⁷, S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁸; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments R^(4a) and R^(4b) are each independently at eachoccurrence selected from: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano,nitro, C(O)R⁷, S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; and R^(4c) and R^(4d)are each independently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments, -(L⁵-L⁴-)_(n)-L³- is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)-,—(CR^(4a)R^(4b))_(j)-L⁴-(CR^(4c)R^(4d))_(k)-,—(CH₂)_(q)-L⁴-[O—(CH₂)_(r)]₁₋₃—(CH₂)_(s)—,—(CH₂)_(q)—[O—(CH₂)_(r)]₁₋₃-L⁴—(CH₂)_(s)—,—(CH₂)_(q)-L⁴-[(CH₂)_(r)—O]₁₋₃—(CH₂)_(s)— or—(CH₂)_(q)—[(CH₂)_(r)—O]₁₋₃-L⁴—(CH₂)_(s)—; wherein o is selected from 3to 10; p is selected from 1 to 3; j is selected from 1 to 3; k is 3 to10; q and s are each independently selected from 0 to 3; and r isselected from 1 to 3; R^(4a) and R^(4b) are each independently at eachoccurrence selected from: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁸, halo, cyano,nitro, C(O)R⁷, S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁸; and R^(4c) and R^(4d)are each independently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments, -(L⁵-L⁴-)_(n)-L³- is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)—,—(CR^(4a)R^(4b))_(j)-L⁴-(CR^(4c)R^(4d))_(k)-,—(CH₂)_(q)-L⁴-[O—(CH₂)_(r)]₁₋₃—(CH₂)_(s)—,—(CH₂)_(q)—[O—(CH₂)_(r)]₁₋₃-L⁴—(CH₂)_(s)—,—(CH₂)_(q)-L⁴-[(CH₂)_(r)—O]₁₋₃—(CH₂)_(s)— or—(CH₂)_(q)—[(CH₂)_(r)—O]₁₋₃-L⁴—(CH₂)_(s)—; wherein o is selected from 3to 10; p is selected from 1 to 3; j is selected from 1 to 3; k is 3 to10; q and s are each independently selected from 0 to 3; and r isselected from 1 to 3; R^(4a) and R^(4b) are each independently at eachoccurrence selected from: H, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano,nitro, C(O)R⁷, S(O)₂OR⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁸; and R^(4c) and R^(4d)are each independently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, NR⁷R⁸, OR⁶, and halo.

In embodiments r is 2.

In embodiments, -(L⁵-L⁴-)_(n)-L³- is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)—, or—(CR^(4a)R^(4b))_(j)-L⁴-(CR^(4c)R^(4d))_(k)-; wherein o is selected from3 to 10; p is selected from 1 to 3; j is selected from 1 to 3; k is 3 to10; wherein R^(4a) and R^(4b) are each independently at each occurrenceselected from: H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, OR⁶, and NR⁷R⁸; andR^(4c) and R^(4d) are each independently at each occurrence selectedfrom: H and methyl.

In embodiments, -(L⁵-L⁴-)_(n)-L³- is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)—, wherein o is selected from3 to 10; p is selected from 1 to 3; wherein R^(4a) and R^(4b) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, OR⁶, and NR⁷R⁸; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H and methyl.

In embodiments L¹, L², L³, L⁴ and L⁵ together form a linker and n, L¹,L², L³, L⁴ and L⁵ are selected such that length of the linker is from 8to 14 atoms.

In embodiments -L⁴- at each occurrence is absent or is selected from:—O—, —S—, NR^(3a)—, —C(O)—, —OC(O)—, —C(O)O—, —NR^(3b)C(O)—,—C(O)NR^(3b), NR^(3b)S(O)₂—, —S(O)₂NR^(3b)—,—OC(O)NR^(3b)—,—NR^(3b)C(O)O—, NR^(3b)C(O)NR^(3b), —CR⁵═CR⁵— and —C≡C—.

In embodiments, L⁴ is at each occurrence absent or is selected from—C(O)NR^(3b)— and —NR^(3b)C(O)—.

In embodiments, L⁴ is at each occurrence absent.

In embodiments, L⁴ is at each occurrence C(O)NR^(3b).

In embodiments, L⁴ is at each occurrence NR^(3b)C(O).

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IV) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (V) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IVa)) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, andR^(W) is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (IVb) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (Va) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In a preferred embodiment the ion of formula (I) may be an ion accordingto formula (Vb) wherein R^(Z) is H, R^(X) is H, R^(Y) is CH₃, and R^(W)is OH.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹- represents —(CH₂)₁₁C(O)NH—,—(CH₂)₁₀C(O)NH—, —(CH₂)₉C(O)NH—, —(CH₂)₈C(O)NH—, —(CH₂)₇C(O)NH,—(CH₂)₉C(O)NHCH₂C(O)NH—, —(CH₂)₈C(O)NHCH₂C(O)NH—,—(CH₂)₇C(O)NHCH₂C(O)NH—, —(CH₂)₆C(O)NHCH₂C(O)NH—,—(CH₂)₅C(O)NHCH₂C(O)NH—, —(CH₂)₄C(O)NHCH₂C(O)NH—,(CH₂)₃C(O)NHCH₂C(O)NH—, —(CH₂)₇C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₈C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₉C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₆C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₅C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₄C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₃C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₉C(O)NHCH₂—, —(CH₂)₈C(O)NHCH₂—, —(CH₂)₇C(O)NHCH₂—,—(CH₂)₆C(O)NHCH₂—, —(CH₂)₅C(O)NHCH₂— and —(CH₂)₄C(O)NHCH₂—.

In embodiments -(L⁵-L⁴-)_(n)-L³-L²-L¹- represents —(CH₂)₁₁C(O)NH—,—(CH₂)₁₀C(O)NH—, —(CH₂)₉C(O)NH—, —(CH₂)₈C(O)NH—, and —(CH₂)₇C(O)NH.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹- represents—(CH₂)₉C(O)NHCH₂C(O)NH—, —(CH₂)₈C(O)NHCH₂C(O)NH—,—(CH₂)₇C(O)NHCH₂C(O)NH—, —(CH₂)₆C(O)NHCH₂C(O)NH—,—(CH₂)₅C(O)NHCH₂C(O)NH—, —(CH₂)₄C(O)NHCH₂C(O)NH—,(CH₂)₃C(O)NHCH₂C(O)NH—.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹- represents—(CH₂)₇C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₈C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₉C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₆C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₅C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₄C(O)NH(CH₂)₂C(O)NH—, and—(CH₂)₃C(O)NH(CH₂)₂C(O)NH—.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹- represents —(CH₂)₉C(O)NHCH₂—,—(CH₂)₈C(O)NHCH₂—, —(CH₂)₇C(O)NHCH₂—, —(CH₂)₆C(O)NHCH₂—,—(CH₂)₅C(O)NHCH₂— and —(CH₂)₄C(O)NHCH₂—.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹-represents —(CH₂)₁₁C(O)NH—,—(CH₂)₇C(O)NH, —(CH₂)₁₀C(O)NH, —(CH₂)₉C(O)NH, —(CH₂)₇C(O)NHCH₂C(O)NH—,—(CH₂)₅C(O)NHCH₂C(O)NH—, (CH₂)₃C(O)NHCH₂C(O)NH—,—(CH₂)₇C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₉C(O)NH(CH₂)₂C(O)NH—,—(CH₂)₄C(O)NH(CH₂)₂C(O)NH—, —(CH₂)₉C(O)NHCH₂—, —(CH₂)₅C(O)NHCH₂— and—(CH₂)₇C(O)NHCH₂—.

In embodiments -(-L⁵-L⁴-)_(n)-L³-L²-L¹- is such that the length of thelinker is 9, 10, 11, 12, 13, or 14 atoms in length.

In embodiments n is an integer selected from 0 or 1.

In embodiments, R^(3a) is at any particular occurrence H. Inembodiments, R^(3a) is at each occurrence H.

In embodiments, R^(3a) is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R^(3a) is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In embodiments, R^(3b) is at any particular occurrence H. Inembodiments, R^(3b) is at each occurrence H.

In embodiments, R^(3b) is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R^(3b) is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In embodiments, R⁵ is at any particular occurrence H. In embodiments, R⁵is at each occurrence H.

In embodiments, R⁴ is at any particular occurrence selected fromC₁-C₄-alkyl, e.g. methyl. In embodiments, R⁴ is at each occurrenceselected from C₁-C₄-alkyl, e.g. methyl.

In embodiments, L³ and L⁵ are unsubstituted.

In embodiments, R⁴ is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R⁴ is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In embodiments, R⁶ is at any particular occurrence H. In embodiments, R⁶is at each occurrence H.

In embodiments, R⁶ is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R⁶ is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In embodiments, R⁷ is at any particular occurrence H. In embodiments, R⁷is at each occurrence H.

In embodiments, R⁷ is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R⁷ is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In embodiments, R⁸ is at any particular occurrence H. In embodiments, R⁸is at each occurrence H.

In embodiments, R⁸ is at any particular occurrence C₁-C₄-alkyl, e.g.methyl. In embodiments, R⁸ is at each occurrence C₁-C₄-alkyl, e.g.methyl.

In an embodiment, the ion according to formula (I) is selected from:

In an embodiment, the ion according to formula (I) is selected from:

The cation of formula (I) will be associated with an anionic counterion. For administration to a subject, the cation of formula (I) will beassociated with a pharmaceutically acceptable anionic counterion. Thefirst aspect of the invention also, therefore, provides a compoundcomprising the ion of formula (I) and a pharmaceutically acceptableanion. The anion may have a single negative charge. For example theanion may be selected from: halo (e.g. Cl, Br and I), BF₄, PF₆,CF₃C(O)O, HC(O)O, HCO₃, (CF₃SO₂)₂N, (C₂F₅)₃PF₃, HSO₄, C₁-C₁₅-alkylSO₄,CH₃C(O)O, CF₃SO₃, Tosyl-O, C(CN)₃, N(CN)₂ or the carboxylate anion of aproteinogenic amino acid. For the avoidance of doubt each anion listedin the preceding sentence possesses a single negative charge. The anionmay have multiple negative charges, e.g. PO₄ ³⁻ or CO₃ ²⁻. The anion maybe derived from a di- or tri-acid, e.g. glutamic acid, succinic acid,malic acid, citric acid, tartaric acid. It may be a mono-carboxylate ofsaid di- or tri-acid. The remaining carboxylic acid groups may be in theform of protonated carboxylic acids, C₁-C₁₂-alkylesters, or they maylikewise be carboxylate anions. Said carboxylate anions may each beaccompanied by a pharmaceutically acceptable metal cation or by anothercation of formula (I).

The anions associated with the cations of the invention can be quitelabile. It may be therefore that the cation of the invention is presentassociated with two or more different anions. Ion exchange processes canbe used to control the identity of the anion associated with the cationof the invention.

In embodiments the anion is Cl, Br, I, PF₆, CF₃C(O)O, or HC(O)O.

In an aspect of the invention, the compounds of the invention are formedical use.

In an aspect, the compounds of the first aspect of the invention are foruse in the treatment of cancer. The compounds may be effective intreating cancer stem cells. The compounds may also be for use inreducing cell proliferation of abnormal cells, such as cancer cells.

In an embodiment, the compounds of the first aspect of the invention arefor use in the treatment of solid tumours and other cancers, e.g.cancers classed as not being solid cancers. Amongst cancers that can betreated by the compounds of the invention are: leukaemia, lymphoma,sarcoma, or carcinoma.

In a further aspect of the invention, there is provided a method for thetreatment of cancer, wherein the method comprises the administration ofa therapeutically effective amount of a compound of the first aspect ofthe invention. The method may be effective in treating cancer stemcells. The method may also be for use in reducing cell proliferation ofabnormal cells, such as cancer cells.

In an embodiment, the method is for the treatment of solid tumours andother cancers, e.g. cancers classed as not being solid cancers. Amongstcancers that can be treated by the methods of the invention are:leukaemia, lymphoma, sarcoma, or carcinoma.

The “treatment” of cancer may be taken to include prevention. Treatmentalso encompasses including any improvement of pathology, symptoms orprognosis that is achieved in respect of cancer in a subject receivingcompounds of the invention. Treatment may be indicated by a partialimprovement of such indications, or by a total improvement (e.g. theabsence of cancer following medical use of the compounds of theinvention).

The “prevention” of cancer may be taken as including the prevention ofthe formation of new tumours, including new primary tumours or newmetastatic tumours. The prevention of cancer may also be taken asencompassing the prevention of the progression of cancer. In thiscontext, prevention of development of cancer may be demonstrated bypreventing an increase in the “stage” of a tumour (using an appropriatecancer staging method) that has been treated using the compounds of theinvention. The prevention of increase in cancer stage may be compared toprogression of an untreated tumour, or compared to the extent ofprogression that would be expected by a clinician in the event that thetumour was not treated.

The compounds of the first aspect of the invention may be for use inincreasing cancer cell death or for decreasing cell proliferation byanother mechanism, such as inhibiting cell replication. The compoundsmay be used for this purpose in vitro or in vivo.

The compounds of the invention may be for use in the modulation ofcancer cells or other dysfunctional cells (such as tumour initiatingcells, stem-like cancer cells, cancer stem cells, or a population ofcells with stem cell-like features that exist in tumors and that giverise to the bulk of tumor cells with more differentiated phenotypes).Accordingly, there is provided a method of modulating cancer cells orother dysfunctional cells in vivo or in vitro by exposing the cancercells or other dysfunctional cells to a compound of the invention. Thecompound may be exposed to the cancer cells or other dysfunctional cellsin an effective amount, for example a therapeutically effective amountsuch as in the case of a method of treatment or an in vivo method.

In another aspect of the invention there is provided a pharmaceuticalcomposition, wherein the composition comprises a compound of theinvention and one or more pharmaceutically acceptable excipients.

In an embodiment, the pharmaceutical composition may be a combinationproduct comprising one or more different pharmaceutically active agents.The one or more additional pharmaceutically active agents may be ananti-cancer agent described below. The one or more pharmaceuticallyactive agents may independently be selected from a different therapeuticclass, e.g. antibiotic, anti-viral, anti-emetic, pain management, etc.

The present invention also contemplates the subject matter contained inthe following numbered clauses:

-   1. A compound comprising an ion of formula (I) or a pharmaceutically    acceptable salt thereof:

wherein

-   R^(W) is H or OH;-   R^(X) is H;-   R^(Y) is H, C₁-C₆-alkyl or C₁-C₆-haloalkyl;-   R^(Z) is H, NR^(Z1)R^(Z2), C₁-C₆-haloalkyl, or halo, wherein R^(Z1)    and R^(Z2) are both independently selected from H or C₁-C₆-alkyl;-   -L¹- is absent or is —CR^(2a)R^(2b)—;-   -L²- is absent or is independently selected from —O—, —S—,    —NR^(3a)—, —C(O)NR^(3b)—, —C(O)—, —OC(O)—, —NR^(3b)C(O)—, NR⁵S(O)₂—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O— and —NR^(3b)C(O)NR^(3c);-   -L³- and -L⁵- are each independently at each occurrence selected    from —C₁-C₄-alkylene-, each alkylene group being unsubstituted or    substituted with from 1 to 10 independently selected R⁴ groups;    provided that any -L³- or -L⁵- group that is attached at each end to    an atom selected from oxygen, nitrogen, sulphur or phosphorous is    —C₂-C₄-alkylene-;-   -L⁴- is independently at each occurrence either absent or is    selected from: —O—, —S—, —NR^(3a)—, —C(O)—, —OC(O)—, —C(O)O—, —SO₂—,    —S(O)—, —NR^(3b)C(O)—, —C(O)NR^(3b), NR^(3b)S(O)₂—, —S(O)₂NR^(3b)—,    —OC(O)NR^(3b)—, —NR^(3b)C(O)O—, NR^(3b)C(O)NR^(3c),    —CR^(5a)═CR^(5b)— and —C≡C—;-   n is an integer selected from 0, 1, 2, 3, 4 and 5;-   wherein L¹, L², L³ L⁴ and L⁵ together form a linker and L¹, L², L³    L⁴ and L⁵ are selected such that length of the linker is from 3 to    16 atoms;-   R^(1a), R^(1b) and R^(1c) are each independently selected from    phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃    to C₈-cycloalkyl, C₁-C₈-alkyl and 5- to 8-membered heterocycloalkyl;    wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered    heteroaryl is optionally substituted with from 1 to 5 independently    selected R^(1d) groups; and wherein said C₃ to C₈-cycloalkyl,    C₁-C₈-alkyl and 5- to 8-membered heterocycloalkyl is optionally    substituted with from 1 to 5 independently selected R^(1e) groups;    provided that R^(1a), R^(1b) and R^(1c) are not each unsubstituted    phenyl;-   R^(1d) is independently at each occurrence selected from:    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷,    C(O)NR⁷R^(7A), halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷    and S(O)₂NR⁷R^(7A);-   R^(1e) is independently at each occurrence selected from: oxo,    C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,    C₃-C₆-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or    10-membered heteroaryl, phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷,    C(O)NR⁷R^(7A), halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷,    S(O)₂R⁷, S(O)₂NR⁷R^(7A), OC(O)NR⁷R^(7A) and NR⁷C(O)OR⁶;-   R^(2a) and R^(2b) are each independently selected from H and    C₁-C₄-alkyl;-   R^(3a), is independently at each occurrence selected from H,    C₁-C₆-alkyl, —C(O)H, —C(O)-C₁-C₆-alkyl and —S(O)₂—C₁-C₆-alkyl-   R^(3b) and R^(3c) are each independently at each occurrence selected    from H and C₁-C₆-alkyl;-   R⁴ is independently at each occurrence selected from: C₁-C₆-alkyl,    C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸,    C(O)OR⁷, C(O)NR⁷R^(7A), halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷,    S(O)R⁷, S(O)₂R⁷ and S(O)₂NR⁷R^(7A);-   R^(5a) and R^(5b) are independently at each occurrence selected from    H, C₁-C₄-alkyl and halo;-   R⁶ is independently at each occurrence selected from: H, C₁-C₆-alkyl    and C₁-C₆-haloalkyl;-   R⁷ and R^(7A) are independently at each occurrence selected from: H    and C₁-C₆-alkyl;-   R⁸ is independently at each occurrence selected from: H,    C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂—C₁-C₆-alkyl;-   and wherein any of the abovementioned alkyl, alkenyl, alkynyl,    cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is    optionally substituted where chemically allowable by from 1 to 4    groups independently selected from oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl,    C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR^(a), NR^(a)R^(b), SR^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), halo, cyano, nitro, C(O)R^(a),    S(O)₂OR^(a), S(O)₂R^(a) and S(O)₂NR^(a)R^(a); wherein R^(a) is    independently at each occurrence selected from: H and C₁-C₆-alkyl;    and R^(b) is independently at each occurrence selected from: H,    C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl.-   2. The compound according to clause 1, wherein R^(Z) is H, R^(X) is    H, R^(Y) is CH₃, and R^(W) is OH.-   3. The compound according to clause 1 or clause 2, wherein L¹ is    absent.-   4. The compound according to clause 1 or clause 2, wherein L¹ is    CR^(2a)R^(2b).-   5. The compound according to any one of clauses 1 to 3, wherein L²    is —NR^(3b)C(O)—.-   6. The compound according to any of clauses 1 to 5, wherein    -(L⁵-L⁴-)_(n)-L³ is —(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d)), wherein    o is selected from 3 to 10; p is selected from 1 to 3; wherein    R^(4a) and R^(4b) are each independently at each occurrence selected    from: H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, OR⁶, and NR⁷R⁸; and R^(4c)    and R^(4d) are each independently at each occurrence selected from:    H and methyl.-   7. The compound according to clause 6, wherein -L⁴- is —NR^(3b)C(O)—-   8. The compound according to clause 6, wherein -L⁴- is absent.-   9. The compound according to any of clauses 1 to 8, wherein n, L¹,    L², L³, L⁴ and L⁵ are selected such that length of the linker is    from 8 to 14 atoms-   10. A compound of any one of clauses 1 to 9, wherein R^(1a), R^(1b)    and R^(1c) are each substituted phenyl.-   11. A compound of any one of clauses 1 to 9, wherein R^(1a), R^(1b)    and R^(1c) are each C₃ to C₈-cycloalkyl.-   12. A compound of any one of clauses 1 to 9, wherein R^(1a), R^(1b)    and R^(1c) are each benzyl.-   13. A compound of any one of clauses 1 to 9, wherein R^(1a) and    R^(1b) are each unsubstituted phenyl and R^(1c) is independently    selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or    10-membered heteroaryl, C₃ to C₈-cycloalkyl, C₁-C₈-alkyl and 5- to    8-membered heterocycloalkyl.-   14. A compound of any one of clauses 1 to 9, wherein R^(1a) and    R^(1b) are each C₃ to C₈-cycloalkyl and R^(1c) is independently    selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered    heteroaryl, C₁-C₈-alkyl and 5- to 8-membered heterocycloalkyl.-   15. A compound of any one of clauses 1 to 9, wherein at least one of    R^(1a), R^(1b) and R^(1c) is C₁-C₆-alkyl.-   16. A compound of clause 15, wherein any of R^(1a), R^(1b) and    R^(1c) that are not C₁-C₆-alkyl are phenyl.-   18. A compound according to any of clauses 1 to 16, for medical use.-   19. The compound according to any of clauses 1 to 16, for use in the    treatment of cancer.-   20. A method for the treatment of cancer, wherein the method    comprises the administration of a therapeutically effective amount    of a compound according to any one of clauses 1 to 16.-   21. A pharmaceutical composition comprising the compound of clauses    1 to 16 and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” or “halogen” refers to an atom selected from fluorine,chlorine, bromine and iodine. “Halo” or “halogen” may refer to an atomselected from Cl and F. “Halo” or “halogen” may refer to fluorine.

The term “alkyl” refers to a linear or branched hydrocarbon chain. Theterm “C₁-C₈ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The term “C₁-C₆ alkyl”refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4,5 or 6 carbon atoms. The term “C₁-C₆ alkyl” for example refers tomethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl,n-pentyl and n-hexyl. The “alkyl” group may be substituted orunsubstituted by one or more substituents. Substituents for the alkylgroup may be halo (for example fluorine, chlorine, bromine and iodine),OH and C₁-C₆ alkoxy. In addition, alkylene groups may be linear orbranched and may have two places of attachment to the remainder of themolecule.

The term “alkylene” refers to a divalent group which is a linear orbranched hydrocarbon chain. With the “alkylene” group being divalent,the group must form two bonds to other groups. The term “C₁-C₈-alkylene”may refer to —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂— or substituted equivalents thereof. Thealkylene group may be unsubstituted or substituted by one or moresubstituents.

The term “cycloalkyl” refers to a saturated hydrocarbon ring system. Theterm “C₃-C₈ cycloalkyl” refers to a saturated hydrocarbon ring systemcontaining 3, 4, 5, 6, 7 or 8 carbon atoms. The ring system may be asingle ring or a bi-cyclic or tri-cyclic ring system. Where the ringsystem is bicyclic one of the rings may be an aromatic ring, for exampleas in indane. The term “cycloalkyl” may refer to, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and indane. The cycloalkyl group may be substituted with oneor more substituents.

The term “haloalkyl” refers to a linear or branched hydrocarbon chainwhich is substituted with at least one halogen atom which areindependently selected at each occurrence from fluorine, chlorine,bromine and iodine. For example, the term “C₁-C₆ haloalkyl” refers to alinear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6carbon atoms. The halogen atom may be substituted at any position on thehydrocarbon chain. The term “C₁-C₆ haloalkyl” may refer to, for example,fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl,trifluoroethyl, chloroethyl, trichloroethyl (such as1,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoropropyl andchloropropyl. The haloalkyl group may be substituted with one or moresubstituents.

The term “alkenyl” refers to a linear or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and having at leasttwo carbon atoms. The term “C₂-C₆ alkenyl” refers to a linear orbranched hydrocarbon chain containing at least one carbon-carbon doublebond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond or doublebonds may be E or Z isomers. The double bond may be present at anypossible position of the hydrocarbon chain. The term “C₂-C₆ alkenyl” mayrefer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl,pentadienyl, hexenyl and hexadienyl. The alkenyl group may besubstituted or unsubstituted by one or more substituents.

The term “cycloalkenyl” refers to an unsaturated hydrocarbon ringsystem. The term “C₃-C₈ cycloalkenyl” refers to an unsaturatedhydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. Thering may contain more than one double bond. The term cycloalkenyl mayrefer to, for example cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl,cycloheptadiene, cyclooctenyl and cycloocatadienyl. The cycloalkenylgroup may be substituted with one or more substituents.

The term “alkynyl” refers to a linear or branched hydrocarbon chaincontaining at least one carbon-carbon triple bond and having at leasttwo carbon atoms. The term “C₂-C₆ alkynyl” refers to a linear orbranched hydrocarbon chain containing at least one carbon-carbon triplebond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond or triplebonds may be present at any possible position of the hydrocarbon chain.The term “C₂-C₆ alkynyl” may refer to, for example, ethynyl, propynyl,butynyl, pentynyl and hexynyl. The alkynyl group may be unsubstituted orsubstituted by one or more substituents.

The term “heteroalkyl” refers to a linear or branched hydrocarbon chaincontaining at least one heteroatom selected from N, O and S which ispositioned between any possible carbon atom in the chain or at the endof the chain. The term “C₁-C₆ heteroalkyl” refers to a linear orbranched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atomsand at least one heteroatom selected from N, O and S which is positionedbetween any possible carbon atom in the chain or at the end of thechain. The heteroalkyl may be attached to another group by theheteroatom or the carbon atom. The term “C₁-C₆ heteroalkyl” may referto, for example, —CH₂NHCH₃, —NHCH₂CH₃ and —CH₂CH₂NH₂. The heteroalkylgroup may be unsubstituted or substituted by one or more substituents.

The term “heterocycloalkyl” refers to a saturated hydrocarbon ringsystem containing at least one heteroatom within the ring systemselected from N, O and S. The term “5- to 8-membered heterocycloalkyl”refers to a saturated hydrocarbon ring with 5, 6, 7, 8, 9 or 10 atomsselected from carbon, N, O and S, at least one being a heteroatom. The“heterocycloalkyl” group may also be denoted as a “3 to 10 memberedheterocycloalkyl” which is also a ring system containing 3, 4, 5, 6, 7,8, 9 or 10 atoms at least one being a heteroatom. The ring system may bea single ring or a bi-cyclic or tri-cyclic ring system. Bicyclic systemsmay be spiro-fused, i.e. where the rings are linked to each otherthrough a single carbon atom; vicinally fused, i.e. where the rings arelinked to each other through two adjacent carbon or nitrogen atoms; orthey may share a bridgehead, i.e. the rings are linked to each other bytwo non-adjacent carbon or nitrogen atoms. Where the ring system isbicyclic one of the rings may be an aromatic ring, for example as inchromane. The “heterocycloalkyl” may be bonded to the rest of themolecule through any carbon atom or heteroatom. The “heterocycloalkyl”may have one or more, e.g. one or two, bonds to the rest of themolecule: these bonds may be through any of the atoms in the ring. Forexample, the “heterocycloalkyl” may be oxirane, aziridine, azetidine,oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide,pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, andchromane.

The term “heterocycloalkenyl” refers to an unsaturated hydrocarbon ringsystem containing at least one heteroatom selected from N, O or S. Theterm “C₃-C₈ heterocycloalkenyl” refers to an unsaturated hydrocarbonring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least oneheteroatom selected from N, O or S. There may be more than one doublebond present. The double bond will typically be between two carbon atomsbut may be between a carbon atom and a nitrogen atom. There may also bemore than 1 heteroatom present. For example, there may be 1, 2 or 3heteroatoms present. The ring system may be a single ring or a bi-cyclicor tri-cyclic ring system. Where the ring system is bicyclic one of therings may be an aromatic ring, for example as in indoline anddihydrobenzofuran. The heterocycloalkenyl may be attached to anothergroup by any carbon or heteroatom. The term heterocycloalkenyl may referto, for example tetrahydropyridine, dihydropyran, dihydrofuran,pyrroline, dihydrobenzofuran, dihydrobenzothiophene and indoline. Theheterocycloalkenyl group may be substituted with one or moresubstituents.

The term “aryl” refers to an aromatic hydrocarbon ring system whichsatisfies Huckel's rule for aromaticity or that contains a ring systemwhich satisfies Huckel's rule for aromaticity. As such an aryl group maybe a single ring or a bi-cyclic or tri-cyclic ring system. The term“aryl” may refer to, for example, phenyl, naphthyl, indane, tetralin andanthracene. The aryl group may be unsubstituted or substituted with oneor more substituents. Any aryl group may be a phenyl ring.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom selected from N, O or S which satisfies Huckel'srule for aromaticity or a ring system that contains a heteroatom and anaromatic hydrocarbon ring. The heteroaryl may be a single ring system ora fused ring system. The term “5-, 6-, 9- or 10-membered heteroaryl”refers to an aromatic ring system within 5, 6, 9, or 10 members selectedfrom carbon, N, O or S either in a single ring or a bicyclic ringsystem. The term heteroaryl may refer to, for example, imidazole,thiazole, oxazole, isothiazole, isoxazole, triazole, tetraazole,thiopheene, furan, thianthrene, pyrrole, benzimidazole, pyrazole,pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone, andisoquinoline.

The term “alkoxy” refers to an alkyl group which is linked to anothergroup by oxygen. The alkyl group may be linear or branched. The term“C₁-C₆ alkoxy” refers to an alkyl group containing 1, 2, 3, 4, 5 or 6carbon atoms which is linked to another group by oxygen. The alkyl groupmay be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term “C₁-C₆ alkoxy” mayrefer to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkylgroup may be substituted or unsubstituted by one or more substituents.

A bond terminating in a “

” means that the bond is connected to another group that is not shown. Abond terminating inside a cyclic structure and not terminating at anatom of the ring structure represents that the bond may be connected toany of the atoms in the ring structure where allowed by valency.

Where a group is substituted, it may be substituted at any point on thegroup where chemically possible and consistent with valencyrequirements. The group may be substituted by one or more substituents.For example, the group may be substituted with 1, 2, 3 or 4substituents. Where there are two or more substituents, the substituentsmay be the same or different. Substituent(s) may be, for example, halo,CN, nitro, oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl,C₁-C₆-haloalkyl, OR^(a), NR^(a)R^(b), SR^(a), C(O)OR^(a),C(O)NR^(a)R^(a), halo, cyano, nitro, C(O)R^(a), S(O)₂OR^(a), S(O)₂R^(a)and S(O)₂NR^(a)R^(a); wherein R^(a) is independently at each occurrenceselected from: H and C₁-C₆-alkyl; and R^(b) is independently at eachoccurrence selected from: H, C₁-C₆-alkyl, C(O)C₁-C₆-alkyl andS(O)₂—C₁-C₆-alkyl.

If chemically possible to do so, a cyclic substituent may be substitutedon a group so as to form a spiro-cycle.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”.

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent. For example the groups below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

The cation of formula (I) will be associated with a pharmaceuticallyacceptable anionic counter ion for administration to a subject.Nevertheless, where either the cation of formula (I) or the anioniccounter ion comprise either basic or acidic groups, those groups maythemselves be protonated or deprotonated and associated with anappropriate counter ion.

Suitable acid addition salts are formed from acids which form non-toxicsalts, for example, acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts,for example include the aluminium, arginine, benzathine, calcium,choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine,olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts ofacids and bases may also be formed, for example, hemisulphate andhemicalcium salts. A review of suitable salts can be found in “Handbookof Pharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

The salt may be an acid addition salt.

The salts may be formate or hydrochloride.

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of the following methods:

-   (i) reacting the compound of formula (I) with the desired acid or    base;-   (ii) removing an acid- or base-labile protecting group from a    suitable precursor of the compound of formula (I) or by ring-opening    a suitable cyclic precursor, for example, a lactone or lactam, using    the desired acid or base; or-   (iii) converting one salt of the compound of formula (I) to another    by reaction with an appropriate acid or base or by means of a    suitable ion exchange column.

The reactions above are typically carried out in solution and theresulting salt may precipitate out and be collected by filtration or maybe recovered by evaporation of the solvent. The degree of ionisation inthe resulting salt may vary from completely ionised to almostnon-ionised.

The compounds may exist in both unsolvated and solvated forms. The term‘solvate’ is used herein to describe a molecular complex comprising thecompound of the invention and a stoichiometric amount of one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

Complexes are contemplated, such as clathrates, drug-host inclusioncomplexes wherein, in contrast to the aforementioned solvates, the drugand host are present in stoichiometric or non-stoichiometric amounts.Complexes of the drug containing two or more organic and/or inorganiccomponents which may be in stoichiometric or non-stoichiometric amountsare also contemplated. The resulting complexes may be ionised, partiallyionised, or non- ionised. A review of such complexes is found in J PharmSci, 64 (8), 1269-1288 by Haleblian (August 1975).

Compounds, ions and salts described in this specification may beisotopically-labelled (or “radio-labelled”). Accordingly, one or moreatoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number typically found in nature.Examples of radionuclides that may be incorporated include ²H (alsowritten as “D” for deuterium), ³H (also written as “T” for tritium),¹¹C, ¹³C, ¹⁴C, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F and the like. The radionuclide that isused will depend on the specific application of that radio-labelledderivative. For example, for in vitro competition assays, ³H or ¹⁴C areoften useful. For radio-imaging applications, ¹¹C or ¹⁸F are oftenuseful. In some embodiments, the radionuclide is ³H. In someembodiments, the radionuclide is ¹⁴C. In some embodiments, theradionuclide is ¹¹C. And in some embodiments, the radionuclide is ¹⁸F.

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds include a number of formula as herein defined, includingall polymorphs and crystal habits thereof, prodrugs and isomers thereof(including optical, geometric and tautomeric isomers) as hereinafterdefined and isotopically-labelled compounds of the invention.

Before purification, the compounds may exist as a mixture of enantiomersdepending on the synthetic procedure used. The enantiomers can beseparated by conventional techniques known in the art. Thus, thecompounds cover individual enantiomers as well as mixtures thereof.

For some of the steps of the process of preparation of the compounds offormula (I), it may be necessary to protect potential reactive functionsthat are not wished to react, and to cleave said protecting groups inconsequence. In such a case, any compatible protecting radical can beused. In particular, methods of protection and deprotection such asthose described by T. W. Greene (Protective Groups in Organic Synthesis,A. Wiley—Interscience Publication, 1981) or by P. J. Kocienski(Protecting groups, Georg Thieme Verlag, 1994), can be used. All of theabove reactions and the preparations of novel starting materials used inthe preceding methods are conventional and appropriate reagents andreaction conditions for their performance or preparation as well asprocedures for isolating the desired products will be well-known tothose skilled in the art with reference to literature precedents and theexamples and preparations hereto.

Also, the compounds as well as intermediates for the preparation thereofcan be purified according to various well-known methods, such as forexample crystallization or chromatography.

The method of treatment or the compound for use in the treatment ofsolid tumours, leukaemia, lymphoma, sarcoma, or carcinoma as definedhereinbefore may be applied as a sole therapy or be a combinationtherapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofsolid tumours, leukaemia, lymphoma, sarcoma, or carcinoma may involve,in addition to the compound of the invention, conventional surgery orradiotherapy or chemotherapy. Such chemotherapy may include one or moreof the following categories of anti-cancer agents:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    such as alkylating agents (for example cis-platin, oxaliplatin,    carboplatin, cyclophosphamide, nitrogen mustard, bendamustin,    melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas);    antimetabolites (for example gemcitabine and antifolates such as    fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,    methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea);    antibiotics (for example anthracyclines like adriamycin, bleomycin,    doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,    dactinomycin and mithramycin); antimitotic agents (for example vinca    alkaloids like vincristine, vinblastine, vindesine and vinorelbine    and taxoids like taxol and taxotere and polokinase inhibitors);    proteasome inhibitors, for example carfilzomib and bortezomib;    interferon therapy; and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan, mitoxantrone and camptothecin);-   (ii) cytostatic agents such as antiestrogens (for example tamoxifen,    fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) anti-invasion agents, for example dasatinib and bosutinib    (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase    plasminogen activator receptor function or antibodies to Heparanase;-   (iv) inhibitors of growth factor function: for example such    inhibitors include growth factor antibodies and growth factor    receptor antibodies, for example the anti-erbB2 antibody trastuzumab    [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1    antibody cetuximab, tyrosine kinase inhibitors, for example    inhibitors of the epidermal growth factor family (for example EGFR    family tyrosine kinase inhibitors such as gefitinib, erlotinib and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine    (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);    inhibitors of the hepatocyte growth factor family; inhibitors of the    insulin growth factor family; modulators of protein regulators of    cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the    platelet-derived growth factor family such as imatinib and/or    nilotinib (AMN107); inhibitors of serine/threonine kinases (for    example Ras/Raf signalling inhibitors such as farnesyl transferase    inhibitors, for example sorafenib, tipifarnib and lonafarnib),    inhibitors of cell signalling through MEK and/or AKT kinases, c-kit    inhibitors, abI kinase inhibitors, PI3 kinase inhibitors, Plt3    kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase    inhibitors; aurora kinase inhibitors and cyclin dependent kinase    inhibitors such as CDK2 and/or CDK4 inhibitors;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, for example the anti-vascular    endothelial cell growth factor antibody bevacizumab (Avastin™);    thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine    kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib    and pazopanib;-   (vi) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2;-   (vii) immunotherapy approaches, including checkpoint inhibitors of    targets such as PD-1, PD-L1 and CTCLA-4, for example antibody    therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan    (Zevalin®), pembrolizumab and ofatumumab; interferons such as    interferon a; interleukins such as IL-2 (aldesleukin); interleukin    inhibitors for example IRAK4 inhibitors; cancer vaccines including    prophylactic and treatment vaccines such as HPV vaccines, for    example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge);    and toll-like receptor modulators for example TLR-7 or TLR-9    agonists; and-   (viii) cytotoxic agents for example fludaribine (fludara),    cladribine, pentostatin (Nipent™);-   (ix) steroids such as corticosteroids, including glucocorticoids and    mineralocorticoids, for example aclometasone, aclometasone    dipropionate, aldosterone, amcinonide, beclomethasone,    beclomethasone dipropionate, betamethasone, betamethasone    dipropionate, betamethasone sodium phosphate, betamethasone    valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol    propionate, cloprednol, cortisone, cortisone acetate, cortivazol,    deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone    sodium phosphate, dexamethasone isonicotinate, difluorocortolone,    fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone    acetonide, fluocinonide, fluocortin butyl, fluorocortisone,    fluorocortolone, fluocortolone caproate, fluocortolone pivalate,    fluorometholone, fluprednidene, fluprednidene acetate,    flurandrenolone, fluticasone, fluticasone propionate, halcinonide,    hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,    hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone    valerate, icomethasone, icomethasone enbutate, meprednisone,    methylprednisolone, mometasone paramethasone, mometasone furoate    monohydrate, prednicarbate, prednisolone, prednisone, tixocortol,    tixocortol pivalate, triamcinolone, triamcinolone acetonide,    triamcinolone alcohol and their respective pharmaceutically    acceptable derivatives. A combination of steroids may be used, for    example a combination of two or more steroids mentioned in this    paragraph;-   (x) targeted therapies, for example PI3Kd inhibitors, for example    idelalisib and perifosine.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products may be administered so that thecombination is provided in a therapeutically effective amount, forexample the compounds of this invention may be administered within atherapeutically effective dosage range described herein and the otherpharmaceutically-active agent may be administered in an amount of lessthan or within its approved dosage range.

According to a further aspect of the invention there is provided apharmaceutical product comprising a compound of the first aspect of theinvention, or a pharmaceutically acceptable salt thereof as definedherein and an additional active agent. The additional active agent maybe a cancer therapy as defined hereinbefore for the combinationtreatment of cancer.

According to a further aspect of the invention there is provided amethod of treating cancer comprising administering a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof simultaneously, sequentially or separately withan additional anti-cancer agent, as defined hereinbefore, to a patientin need thereof.

According to a further aspect of the invention there is provided acompound of the invention, or a pharmaceutically acceptable salt thereoffor use simultaneously, sequentially or separately with an additionalanti-cancer agent as defined herein, in the treatment of cancer.

According to another aspect of the invention there is provided a use ofthe compound of the invention in combination with an anti-cancer agent,such as those hereinbefore described. The compound of formula (I) may beused simultaneously, sequentially or separately with the additionalanti-cancer agent. The use may be in a single combination productcomprising the compound of the invention and the anti-cancer agent. Theadditional anti-cancer agent may be a further compound of the firstaspect of the invention.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof the invention simultaneously, sequentially or separately with ananti-cancer agent, as defined hereinbefore. The method may comprisecombining the compound of the invention and the anti-cancer agent in asingle dosage form. Alternatively, the method may comprise providing theanti-cancer agent as separate dosage forms.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with, or previous to, this specification inconnection with this application and which are open to public inspectionwith this specification, and the contents of all such papers anddocuments are incorporated herein by reference.

Methods for Synthesizing Compounds

Certain ions of the invention can be synthesised according to oranalogously to methods described in the General Schemes below and/byother techniques known to those of ordinary skill in the art. Certainions of the invention can be synthesised according to or analogously tothe methods described in the Examples.

Certain Ions of Formula (I) Can be Made by Scheme A

Reaction of aniline (1) with phosphonium acid (2) can furnishphosphonium amide (3). The reaction can be performed using standardpeptide coupling agents, such as1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez's reagent) orpropylphosphoric anhydride in the presence of a base, such as DIEA orNaHCO₃ in a chlorinated solvent, such as DCM at a temperature from 10 to30° C. Phosphonium acid (2) can be prepared from reaction of halide (4)(X═Cl or Br) with phosphine PR^(1a)R^(1b)R^(1c) (10). The reaction canbe accomplished by heating in an organic solvent, such as MeCN at atemperature from 50 to 80° C.

Certain Ions of Formula (I) Can be Made by Scheme B

Reaction of benzyl amine (5) with 2,5-dioxopyrrolidin-1-yl phosphonium(7) can furnish phosphonium amide (6). The reaction can be performed inthe presence of a base, such as Et₃N, in an organic solvent, such as DCMfrom 10 to 30° C. The 2,5-dioxopyrrolidin-1-yl phosphonium (7) can beprepared from reaction of phosphonium acid (2) with N-hydroxysuccinimidein the presence of 1,3-dicyclohexylcarbodiimide in a chlorinatedsolvent, such as DCM, at a temperature from 10 to 30° C.

Certain Ions of Formula (I) Can be Made by Scheme C

Reaction of aniline (1) with halo sulphonic acid (8) (where X═Cl or Br;L⁶ is a C₂-C₁₃-alkylene group optionally substituted with from 0 to 10R⁴ groups) can furnish halo sulphonamide (9). The reaction can beperformed using SOCl₂ in an organic solvent, such as DMF or DCM, at atemperature from 20 to 60° C. Reaction of phosphine (10) with halosulphonamide (9) can deliver phosphonium sulphonamide (11). The reactioncan be accomplished by heating in an organic solvent, such as MeCN at atemperature from 50 to 80° C.

Certain Ions of Formula (I) Can be Made by Scheme D

Reaction of benzyl amine (5) with halo sulphonic acid (8) (where X═Cl orBr) can furnish halo sulphonamide (12). The reaction can be performedusing SOCl₂ in an organic solvent, such as DMF or DCM, at a temperaturefrom 20 to 60° C. Reaction of phosphine (10) with halo sulphonamide (12)can deliver phosphonium sulphonamide (13). The reaction can beaccomplished by heating in an organic solvent, such as MeCN at atemperature from 50 to 80° C.

Certain Ions of Formula (I) Can be Made by Scheme E

Aniline (1) can be converted to its diazonium salt (14) through theaction of butyl nitrite in the presence of an acid, such as HCl. Thereaction can be performed in an alcoholic solvent, such as MeOH, at atemperature from −5 to 0° C. Reaction of diazonium salt (14) with CO inthe presence of a Pd catalyst, such as Pd(OAc)₂ can deliver carboxylicacid (15). The reaction can be accomplished in an anhydrous organicsolvent, such as DMF, at room temperature. Reaction of carboxylic acid(15) with phosphonium amine (16) (L⁷ is a C₂-C₁₃-alkylene groupoptionally substituted with from 0 to 10 R⁴ groups) can furnishphosphonium amide (17). The reaction can be performed using standardpeptide coupling agents, such asN-(3-dimethylaminopropyl)-N-ethylcarbodiimide HCl (EDCI) and HOBt in anorganic solvent, such as DMF, at room temperature.

Phosphonium Amine (16) Can Synthesised by Scheme F.

Reaction of halo isoindoline-1,3-dione (18) (where X═Cl or Br) withphosphine (10) can deliver phosphonium isoindoline-1,3-dione (19). Thereaction can be performed by heating in an organic solvent, such asMeCN, at a temperature from 50 to 80° C. Reaction of the phosphoniumisoindoline-1,3-dione (19) with hydrazine hydrate in an alcoholicsolvent, such as EtOH, at a temperature from 50 to 75° C. can furnishphosphonium amine (16).

Certain Ions of Formula (I) Can be Made by Scheme G

Diazonium salt (14) (prepared as described in Scheme E) can be convertedto the xanthate (20). The reaction can be accomplished by treatment withpotassium ethyl xanthate in H₂O in the presence of a base, such asNa₂CO₃, at a temperature from 25 to 60° C. Hydrolysis of xanthate (20)to generate thiol (21) can be performed with aqueous NaOH in EtOH orNaOMe in MeOH, followed by pH adjustment using aqueous HCl. The reactioncan be conducted at room temperature. Oxidation of the thiol (21) tosulphonic acid (22) can be accomplished using Oxone in the presence of abase, such as NaHCO₃ in a solvent mixture of MeCN/H₂O at roomtemperature. Reaction of sulphonic acid (22) with phosphonium amine (16)(prepared as described in Scheme F) can furnish phosphonium sulphonamide(23). The reaction can be performed using reagents standard forsulphonamide formation, such as cyanuric chloride in the presence of abase, such as Et₃N, in an organic solvent, such as MeCN, at roomtemperature.

Certain Ions of Formula (I) Can be Made by Scheme H

Reaction of aniline (1) with phosphonium chlorocarbonate (27) (L⁸ is aC₂-C₁₃-alkylene group optionally substituted with from 0 to 10 R⁴groups) can furnish phosphonium carbamate (24). The reaction can beaccomplished in the presence of a base, such as pyridine, in an organicsolvent, such as DCM, at a temperature from 0° C. to room temperature.Phosphonium chloroacetate (27) can be synthesised from phosphoniumalcohol (26) through treatment with triphosgene in the presence of abase, such as DIEA, in an organic solvent, such as THF, at a temperaturefrom −5 to 5° C. Phosphonium alcohol (26) can be synthesised from haloalcohol (25) (where X═Cl or Br) and phosphine PR^(1a)R^(1b)R^(1c) (10).The reaction can be accomplished by heating in an organic solvent, suchas MeCN, at a temperature from 50 to 80° C.

Certain Ions of Formula (I) Can be Made by Scheme I

Iodination of tetracycline (28) can furnish iodide (29). The reactioncan be accomplished by the treatment with I₂ in the presence of Ag₂SO₄and concentrated H₂SO₄ (few drops) in an organic solvent, such as MeOH,at room temperature. Iodide (29) can be converted to acetic acid (30)through reaction with AgOAc and Pd(OAc)₂ in acetic acid, at atemperature from 100 to 130° C. Reaction of carboxylic acid (30) withphosphonium amine (16) can furnish phosphonium amide (31). The reactioncan be performed using standard peptide coupling agents, such asN-(3-dimethylaminopropyl)-N-ethylcarbodiimide HCl (EDCI) and HOBt in anorganic solvent, such as DMF, at room temperature. Phosphonium amine(16) can synthesised by Scheme F.

Replacement of amine (1) in Scheme A with amine (32) can provide thecorresponding phosphonium amide (33), a subset of ions of formula (I).

Replacement of benzyl amine (5) in Scheme B with benzyl amine (34) canprovide phosphonium amide (35), a subset of ions of formula (I).

Replacement of amine (1) in Scheme C with amine (32) can providephosphonium sulphonamide (36), a subset of ions of formula (I).

Replacement of benzyl amine (5) in Scheme D with benzyl amine (34) canprovide phosphonium sulphonamide (37), a subset of ions of formula (I).

Replacement of diazonium (14) in Scheme E with diazonium (38) canprovide phosphonium amide (39), a subset of ions of formula (1).

Replacement of diazonium (14) in Scheme G with diazonium (38) canprovide phosphonium sulphonamide (40), a subset of ions of formula (1).

Replacement of amine (1) in Scheme H with amine (32) can providephosphonium carbamate (41), a subset of ions of formula (I).

Replacement of iodide (29) in Scheme I with iodide (42) can providephosphonium amide (43), a subset of ions of formula (I).

Experimental

Analytical Methods

-   NMR spectra were obtained on a 400 MHz Bruker AV III (Method A)-   UPLC/MS was carried out using a Waters Acquity QDa mass detector and    Method A, C or Waters SQ mass detector and Method B

Method A

-   Column: Waters Acquity UPLC CSH C18, 1.7 μm, 2.1×30 mm; Gradient    Eluent: 5-95%-   MeCN/H₂O containing 0.1% HCOOH; Time: 0-10 min

Method B

-   Column: Waters Acquity UPLC CSH C18, 1.7 μm, 2.1×30 mm; Gradient    Eluent: 5-95%-   MeCN/H₂O containing 0.1% HCOOH; Time: 0-15 min

Method C

-   Column: Waters Acquity UPLC CSH C18, 1.7 μm, 2.1×30 mm; Gradient    Eluent: 5-95%-   MeCN/H₂O containing 0.1% HCOOH; Time: 0-3 min-   Preparative HPLC was carried out using a ZQ Mass Spectrometer and    Method A or B

Method A

-   Waters X-Select Prep-C18, 5 μm, 19×50 mm eluting with MeCN/H₂O/0.1%    HCOOH

Method B

-   Waters X-Select Prep-C18, 5 μm, 19×50 mm eluting with MeCN/H₂O/0.2%    HCl

Abbreviations

The following abbreviations have been used throughout the specificationin the Examples and in the description;N-(3-dimethylaminopropyl)-N-ethylcarbodiimide HCl (EDCI);Hydroxybenzotriazole (HOBt); Methyl tert-butyl ether (MTBE);N,N-Diisopropylethylamine (DIEA); Dichloromethane (DCM);Dimethylformamide (DMF); N-Methyl-2-pyrrolidone (NMP); Methyl tert-butylether (MTBE).

Example1—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)tris(4-methoxyphenyl)phosphoniumformate (11-carboxyundecyl)tris(4-methoxyphenyl)phosphonium bromide

A mixture of 12-bromododecanoic acid (302 mg, 1.08 mmol) andtris(4-methoxyphenyl)phosphine (400 mg, 1.14 mmol) in degassed MeCN (5mL) under N₂ was heated at 80° C. for 3 d. On cooling the solvent wasremoved in vacuo and the resulting residue purified by columnchromatography eluting with 0-10% MeOH in DCM to give(11-carboxyundecyl)tris(4-methoxyphenyl)phosphonium bromide (545 mg,80%) as a white solid.

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)tris(4-methoxyphenyl)phosphoniumformate (Example 1)

To a solution of 11-carboxyundecyl)tris(4-methoxyphenyl)phosphoniumbromide (prepared as described in step (a)) (249 mg, 0.40 mmol) in DCM(1 mL) was added 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez'sreagent) (57 μL, 0.43 mmol). The resulting mixture was stirred at roomtemperature for 30 min and then added dropwise to a stirred suspensionof 9-aminodoxycyline sulphate (200 mg, 0.36 mmol) and NaHCO₃ (301 mg,3.59 mmol) in NMP (1 mL). The resulting reaction mixture was stirred atroom temperature for 30 min, then filtered through a phase separator,which was washed with EtOH. The combined organics were concentratedunder reduced pressure and dripped into cold MTBE (500 mL). Theresulting precipitate was collected by filtration, washed with freshMTBE and dried under vacuo overnight. The crude product was purified bypreparative HPLC (Method A) to give(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)tris(4-methoxyphenyl)phosphoniumformate (35 mg, 9% yield) as a brown solid.

1H NMR (Method A) (CD₃OD): δ (delta) ppm 8.31 (s, 1H), 8.12 (d, J=8.5Hz, 1H), 7.69-7.59 (m, 6H), 7.27-7.20 (m, 6H), 6.90 (d, J=8.5 Hz, 1H),3.91 (s, 9H), 3.62 (dd, J=10.4, 7.8 Hz, 1H), 3.21-3.08 (m, 2H), 2.84 (s,4H), 2.79-2.69, (m, 1H), 2.69-2.52 (m, 3H), 2.48-2.38 (m, 2H), 1.77-1.13(m, 23H); 31P NMR (162 MHz, CD₃OD) δ (delta) ppm +21.41 (s); LC-MS(Method A) 992.7 [M]⁺; RT 3.65 min

Example2—(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)(methyl)diphenylphosphoniumchloride (7-carboxyheptyl)(methyl)diphenylphosphonium bromide

A suspension of 8-bromodecanoic acid (1.06 g, 4.76 mmol) in MeCN (10 mL)was heated at 40° C. until solubilised. The resulting solution wasdegassed with bubbling N₂ for 30 min and then treated withmethyldiphenylphosphine (0.93 mL, 4.99 mmol). The resulting reactionmixture was heated at 90° C. under N₂ for 16 h. On cooling the reactionmixture was added dropwise to a stirred solution of MTBE (100 mL) andthe resulting gum collected by removal of excess MTBE and dried to give((7-carboxyheptyl)(methyl)diphenylphosphonium bromide (1.8 g, 85%) as apale orange gum, which was used in the next step without any furtherpurification.

LC-MS (Method C) 343.3 [M]⁺; RT 0.80 min

(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)(methyl)diphenylphosphoniumchloride

To a solution of (7-carboxyheptyl)(methyl)diphenylphosphonium bromide(prepared as described in Example 2 step (a)) (205 mg, 0.48 mmol) in DCM(2.7 mL) was added 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez'sreagent) (80 μL, 0.61 mmol). The resulting mixture was stirred at roomtemperature for 10 min and then added dropwise to a stirred suspensionof 9-aminodoxycyline hydrochloride (200 mg, 0.40 mmol) in DMF (1 mL).The resulting reaction mixture was stirred at room temperature for 20min and then treated dropwise with 4 M HCl in dioxane (0.50 mL, 2.02mmol). The resulting solution was added dropwise to a stirred solutionof MTBE (100 mL). The resulting brown oil was isolated by removal ofexcess MTBE and dissolved in MeOH (2 mL), which on dropwise addition tofresh MTBE (100 mL) gave a beige solid. The solid was isolated byfiltration under N₂ and slurried in MeCN (10 mL) at 70° C. After 1 h thehot slurry was filtered and the solid collected was further purified bypreparative HPLC (Method B) to give the title compound (35 mg) as ayellow solid as its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +24.30 (s); LC-MS (Method B)784 [M]⁺; RT 2.71 min

Example3—(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)dimethylphenylphosphoniumchloride (7-carboxyheptyl)dimethylphenylphosphonium bromide

Prepared following the procedure in Example 2 step (a) but usingdimethylphenylphosphine. (7-carboxyheptyl)dimethylphenylphosphoniumbromide was isolated as a white solid, which was used in the next stepwithout further purification.

(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)dimethylphenylphosphoniumchloride

Prepared following the procedure in Example 2 step (b) but using(7-carboxyheptyl)dimethylphenylphosphonium bromide (prepared asdescribed in Example 3 step (a)). Title compound isolated as a yellowbrown solid as its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +26.11 (s); LC-MS (Method B)722 [M]⁺; RT 2.11 min

Example4—(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)trimethylphosphoniumchloride (7-carboxyheptyl)trimethylphosphonium bromide

Prepared following the procedure in Example 2 step (a) but usingtrimethylphosphine (1 M in toluene).(7-carboxyheptyl)trimethylphosphonium bromide was isolated as a whitesolid, which was used in the next step without further purification.

LC-MS (Method C) 219.3 [M]⁺; RT 0.18 min

(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)trimethylphosphoniumchloride

To a solution of (7-carboxyheptyl)trimethylphosphonium bromide (preparedas described in Example 4 step (a)) (145 mg, 0.48 mmol) in DCM (2.7 mL)was added 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez's reagent)(80 μL, 0.61 mmol). Further DCM (1 mL) was added and the resultingmixture stirred at room temperature. After 20 min the reaction mixturewas added dropwise to a stirred suspension of 9-aminodoxycylinehydrochloride (200 mg, 0.40 mmol) in DMF (4.1 mL). The resultingreaction mixture was stirred at room temperature for 20 min and thentreated dropwise with 4 M HCl in dioxane (0.50 mL, 2.02 mmol). Theresulting solution was added dropwise to a stirred solution of MTBE (100mL). The resulting brown oil was isolated by removal of excess MTBE anddissolved in MeOH (2 mL), which on dropwise addition to fresh MTBE (100mL) gave a brown solid. The solid was isolated by filtration under N₂and slurried in MeCN (10 mL) at 70° C. After 1 h the hot slurry wasfiltered and the hot filtrate concentrated under vacuo to give a darkgreen residue, which was further purified by preparative HPLC (Method B)to give the title compound (35 mg) as a yellow brown solid as its HClsalt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +27.94 (s); LC-MS (Method B)660 [M]⁺; RT 1.51 min

Example5—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)(methyl)diphenylphosphoniumchloride (11-carboxyundecyl)(methyl)diphenylphosphonium bromide

Prepared following the procedure in Example 2 step (a) but using12-bromododecanoic acid. (11-carboxyundecyl)(methyl)diphenylphosphoniumbromide was isolated as a pale orange gum, which was used in the nextstep without further purification.

LC-MS (Method C) 399.4 [M]⁺; RT 1.08 min

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)(methyl)diphenylphosphoniumchloride

Prepared following the procedure in Example 4 step (b) but using(11-carboxyundecyl)(methyl)diphenylphosphonium bromide (prepared asdescribed in Example 5 step (a)). Title compound isolated as a yellowsolid as its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +24.3 (s); LC-MS (Method B) 840[M]⁺; RT 3.97 min

Example6—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)trimethylphosphoniumchloride (11-carboxyundecyl)trimethylphosphonium bromide

Prepared following the procedure in Example 2 step (a) but using12-bromododecanoic acid and trimethylphosphine (1 M in toluene).(11-carboxyundecyl)trimethylphosphonium bromide was isolated as a whitesolid, which was used in the next step without further purification.

LC-MS (Method C) 275.3 [M]⁺; RT 0.82 min

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)trimethylphosphoniumchloride

Prepared following the procedure in Example 2 step (b) but using((11-carboxyundecyl)trimethylphosphonium bromide (prepared as describedin Example 6 step (a)). Title compound isolated as a yellow brown solidas its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +27.91 (s); LC-MS (Method B)716 [M]⁺; RT 3.86 min

Example7—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)tris(3-methylphenyl)phosphoniumchloride (11-carboxyundecyl)tris(3-methylphenyl)phosphonium bromide

Prepared following the procedure in Example 1 step (a) but usingtri(m-tolyl)phosphine.(11-carboxyundecyl)tris(3-methylphenyl)phosphonium bromide was isolatedas a tar and used in the next step without any further purification.

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)tris(3-methylphenyl)phosphoniumchloride

Prepared following the procedure in Example 4 step (b) but using(11-carboxyundecyl)tris(3-methylphenyl)phosphonium bromide (prepared asdescribed in Example 7 step (a)). Title compound isolated as a yellowbrown solid as its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +23.60 (s); LC-MS (Method B)944.8 [M]⁺; RT 5.21 min

Example8—(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride 4-(diphenylphosphonyl)-1-methyl-1H-pyrazole

Butyllithium (2.5 M in hexanes) (2.73 mL, 6.83 mmol) was added dropwiseto a solution of 4-bromo-1-methyl-1H-pyrazole (0.64 mL, 6.21 mmol) intoluene (10 mL) at −78° C. The resulting reaction mixture was allowed towarm to 0° C. After stirring for 15 min chlorodiphenylphosphine (1.27mL, 6.83 mmol) was added dropwise and the reaction mixture allowed towarm to room temperature. After stirring for 1 h the reaction mixturewas diluted with EtOAc (10 mL) and washed with H₂O (10 mL) followed bybrine (10 mL). The resulting organics were dried over MgSO₄ and solventremoved under vacuo. The resulting residue was purified bychromatography eluting with 0-50% TBME in isohexane to give4-(diphenylphosphonyI)-1-methyl-1H-pyrazole (0.78 g, 47%) as acolourless oil, which was used in the next step without any furtherpurification.

LC-MS (Method C) 267 [M+H]⁺; RT 1.56 min

(7-carboxyheptyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide

Prepared following the procedure in Example 1 step (a) but using4-(diphenylphosphonyl)-1-methyl-1H-pyrazole (prepared as described inExample 7 step (a)). Purification was by 0-10% MeOH in DCM.(7-carboxyheptyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromidewas isolated as colourless gum and used in the next step without anyfurther purification.

LC-MS (Method C) 409 [M]⁺; RT 0.85 min

(7-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}heptyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride

Prepared following the procedure in Example 2 step (b) but using(7-carboxyheptyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide(prepared as described in Example 8 step (b)). Title compound isolatedas a yellow brown solid as its HCl salt.

31P NMR (162 MHz, DMSO-d₆) δ (delta) ppm +13.45 (s); LC-MS (Method B)850 [M]⁺; RT 3.86 min

Example9—(8-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}octyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride (8-carboxyoctyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumbromide

Prepared following the procedure in Example 1 step (a) but using4-(diphenylphosphonyl)-1-methyl-1H-pyrazole (prepared as described inExample 8 step (a)) and 9-bromononanoic acid. Purification was by silicacolumn chromatography eluting with 0-10% MeOH in DCM.(8-carboxyoctyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromidewas isolated as a clear oil and used in the next step without anyfurther purification.

LC-MS (Method C) 423 [M]⁺; RT 0.91 min

(8-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}octyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride

To a solution of(8-carboxyoctyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide(prepared as described in Example 9 step (a)) (150 mg, 0.30 mmol) in DCM(1.3 mL) was added 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez'sreagent) (52.6 μL, 0.40 mmol). The resulting mixture was stirred at roomtemperature. After 1 h further 1-chloro-N,N-2-trimethyl-1-propenylamine(52.6 μL, 0.40 mmol) was added and stirring continued. After 30 min thereaction mixture was added dropwise to a stirred solution of9-aminodoxycyline hydrochloride (99 mg, 0.2 mmol) in DMF (0.46 mL). Theresulting reaction mixture was stirred at room temperature for 1 h andthen added dropwise to MTBE (50 mL). Following sonication, a yellowsolid was isolated by filtration, which was taken up in DCM (20 mL)/H₂O(20 mL). The aqueous layer was separated and extracted with DCM (3×20mL). The combined organic phases were extracted with H₂O (3×20 mL). Thecombined aqueous phases were extracted with n-BuOH (3×20 mL) and thecombined n-BuOH extracts concentrated under vacuo. The resulting residuewas taken up in toluene and solvent removed under reduced pressure togive a brown residue, which was purified by preparative HPLC (Method A).The resulting brown solid was taken up in MeOH (2 mL) and filteredthrough an Amberlite IRA-400(CI) ion exchange resin. The collected MeOHwas recycled through the column 3×, followed by a fresh volume of MeOH.The combined MeOH washings were concentrated under reduced pressure togive the title compound (48 mg) as a yellow brown solid as its HCl salt.

LC-MS (Method B) 864 [M]⁺; RT 3.18 min

Example10—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride(11-carboxyundecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide

Prepared following the procedure in Example 1 step (a) but using4-(diphenylphosphonyl)-1-methyl-1H-pyrazole (prepared as described inExample 8 step (a)) and 12-bromododecanoic acid. Purification was bysilica column chromatography eluting with 0-10% MeOH in DCM.(11-carboxyundecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromidewas isolated as a clear oil and used in the next step without anyfurther purification.

LC-MS (Method C) 465 [M]⁺; RT 1.54 min

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride

Prepared following the procedure in Example 9 step (b) using(11-carboxyundecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide(prepared as described in Example 10 step (a)). Title compound wasisolated as a yellow solid as its HCl salt.

LC-MS (Method B) 907 [M]⁺; RT 4.15 min

Example11—(9-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}nonyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride (9-carboxynonyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumbromide

Prepared following the procedure in Example 1 step (a) but using4-(diphenylphosphonyl)-1-methyl-1H-pyrazole (prepared as described inExample 8 step (a)) and 10-bromodecanoic acid. Purification was bysilica column chromatography eluting with 0-10% MeOH in DCM.(9-carboxynonyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromidewas isolated as a light brown oil and used in the next step without anyfurther purification.

LC-MS (Method C) 437 [M]⁺; RT 0.98 min

(9-{[(5R,5a R,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}nonyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride

Prepared following the procedure in Example 9 step (b) using(9-carboxynonyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide(prepared as described in Example 11 step (a)). Title compound wasisolated as a yellow solid as its HCl salt.

LC-MS (Method B) 879 [M]⁺; RT 3.55 min

Example12—(10-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}decyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride (10-carboxydecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumbromide

Prepared following the procedure in Example 1 step (a) but using4-(diphenylphosphonyl)-1-methyl-1H-pyrazole (prepared as described inExample 8 step (a)) and 11-bromoundecanoic acid. Purification was bysilica column chromatography eluting with 0-10% MeOH in DCM.(10-carboxydecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromidewas isolated as a clear oil and used in the next step without anyfurther purification.

LC-MS (Method C) 451 [M]⁺; RT 1.05 min

(10-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}decyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphoniumchloride

Prepared following the procedure in Example 9 step (b) using(10-carboxydecyl)(1-methyl-1H-pyrazol-4-yl)diphenylphosphonium bromide(prepared as described in Example 12 step (a)). Title compound wasisolated as a brown solid as its HCl salt.

LC-MS (Method B) 893 [M]⁺; RT 3.85 min

Example13—(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)diphenyl(propan-2-yl)phosphoniumchloride (11-carboxyundecyl)diphenyl(propan-2-yl)phosphonium bromide

Prepared following the procedure in Example 2 step (a) but usingisopropyldiphenylphosphine and 12-bromododecanoic acid.(11-carboxyundecyl)diphenyl(propan-2-yl)phosphonium bromide was isolatedas a colourless gum and used in the next step without any furtherpurification.

LC-MS (Method C) 427 [M]⁺; RT 1.15 min

(11-{[(5R,5aR,6S,6aR,7S,10aS)-9-carbamoyl-7-(dimethylamino)-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydrotetracen-2-yl]carbamoyl}undecyl)diphenyl(propan-2-yl)phosphoniumchloride

Prepared following the procedure in Example 9 step (b) using(11-carboxyundecyl)diphenyl(propan-2-yl)phosphonium bromide (prepared asdescribed in Example 13 step (a)). Title compound was isolated as ayellow solid as its HCl salt.

LC-MS (Method B) 869 [M]⁺; RT 4.21 min

Inhibition of Proliferation Assay Cell Confluence

The confluence value is a surrogate for cell proliferation and growth.The value is expressed as a percent confluence, which represents thefraction of culture dish-surface that is occupied by cells. As thenumber of cells in the dish increases over time due to proliferation, sowill their coverage of that surface increase. Expansion of the cellpopulation on the cell culture-dish surface and confluence have mostly alinear relationship until the cells on the plate surface begin to reachsaturation or maximum density.

Confluence is determined based on image analysis. Image based softwarecan identify objects in the image field base on changes to pixel densityin a grey scale image. The software can then assign a mask to thosepixels within the object. Objects can be ‘gated’ out based on size andshape. To determine cell confluence, images of cells are first masked asobjects. The surface area of the image that is masked is measured andcompared to the total surface area of the culture dish surface to obtaina percent confluence.

MDA-231 cancer cells were obtained from ATCC. Cells were cultured inDulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FetalBovine Serum (FBS), 2 mM Glutamax, 1 mM Non Essential Amino Acid (NEAA)solution and 1 mM sodium pyruvate. Compounds were dissolved in DMSO at10 mM and diluted in cellular medium and tested at 10 uM. Final DMSOconcentrations were 50.1%. Images were acquired with an IncuCyte LiveCell Imaging microscopy (Essen Bioscience) at every 3 h under cellculture conditions with 10× objective over 4-5 d. Cell confluence wascalculated from one field of view per well using the IncuCyte in-builtalgorithm. Relative confluence values were obtained by normalising eachvalue to the time zero value in each sample.

Concentration μM Example (micromolar) % Confluence Doxycycline 50 91Doxycycline 10 98.7 1 10 17 2 10 91.7 3 10 62.5 4 10 111.8 5 10 24.9 610 57.7 7 10 29.4 8 10 45.6 9 10 55.5 10 10 12.4 11 10 70.1 12 10 45.413 10 35.1

It is anticipated that further compounds of the invention willdemonstrate positive cell confluence data.

1. A compound comprising an ion of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein R^(W) is H or OH; R^(X) is H; R^(Y) is H, C₁-C₆-alkyl orC₁-C₆-haloalkyl; R^(Z) is H, NR^(Z1)R^(Z2), C₁-C₆-haloalkyl, or halo,wherein R^(Z1) and R^(Z2) are both independently selected from H orC₁-C₆-alkyl; -L¹- is absent or is —CR^(2a)R^(2b)—; -L²- is absent or isindependently selected from —O—, —S—, —NR^(3a)—, —C(O)NR^(3b)—, —C(O)—,—OC(O)—, —NR^(3b)C(O)—, NR⁵S(O)₂—, —OC(O)NR^(3b)—, —NR^(3b)C(O)O— and—NR^(3b)C(O)NR^(3c); -L³- and -L⁵- are each independently at eachoccurrence selected from —C₁-C₄-alkylene-, each alkylene group beingunsubstituted or substituted with from 1 to 10 independently selected R⁴groups; provided that any -L³- or -L⁵- group that is attached at eachend to an atom selected from oxygen, nitrogen, sulphur or phosphorous is—C₂-C₄-alkylene-; -L⁴- is independently at each occurrence either absentor is selected from: —O—, —S—, —NR^(3a)-, —C(O)—, —OC(O)—, —C(O)O—,—SO₂-, —S(O)—, —NR^(3b)C(O)—, —C(O)NR^(3b), NR^(3b)S(O)₂—,—S(O)₂NR^(3b)—, —OC(O)NR^(3b)—, —NR^(3b)C(O)O—, NR^(3b)C(O)NR^(3c),—CR^(5a)═CR^(5b)— and —C≡C—; n is an integer selected from 0, 1, 2, 3, 4and 5; wherein L¹, L², L³ L⁴ and L⁵ together form a linker and L¹, L²,L³ L⁴ and L⁵ are selected such that length of the linker is from 3 to 16atoms; R^(1a), R^(1b) and R^(1c) are each independently selected fromphenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-membered heteroaryl, C₃ toC₈-cycloalkyl, C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl;wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10-memberedheteroaryl is optionally substituted with from 1 to 5 independentlyselected R^(1d) groups; and wherein said C₃ to C₈-cycloalkyl,C₁-C₈-alkyl and 4- to 8-membered heterocycloalkyl is optionallysubstituted with from 1 to 5 independently selected R^(1e) groups;provided that R^(1a), R^(1b) and R^(1c) are not each unsubstitutedphenyl; wherein R^(1a) and R^(1b) are optionally connected to each othervia a bond or a group selected from —O—, NR^(6a), and C₁-C₃-alkylene;R^(1d) is independently at each occurrence selected from: C₁-C₆-alkyl,C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, 5- to8-membered heterocycloalkyl, 5-, 6-, 9- or 10-membered heteroaryl,phenyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷,S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷ and S(O)₂NR⁷R⁷; R^(1e) is independently ateach occurrence selected from: oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl,C₂-C₆-alkenyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, 5- to 8-memberedheterocycloalkyl, 5-, 6-, 9- or 10-membered heteroaryl, phenyl, OR⁶,SR⁷, NR⁷R⁸, C(O)OR⁷, C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷,S(O)R⁷, S(O)₂R⁷, S(O)₂NR⁷R⁷, OC(O)NR⁷R⁷ and NR⁷C(O)OR⁶; R^(2a) andR^(2b) are each independently selected from H and C₁-C₄-alkyl; R^(3a),is independently at each occurrence selected from H, C₁-C₆-alkyl,—C(O)H, —C(O)—C₁-C₆-alkyl and —S(O)₂—C₁-C₆-alkyl R^(3b) and R^(3c) areeach independently at each occurrence selected from H and C₁-C₆-alkyl;R⁴ is independently at each occurrence selected from: C₁-C₆-alkyl,C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl, OR⁶, SR⁷, NR⁷R⁸, C(O)OR⁷,C(O)NR⁷R⁷, halo, cyano, nitro, C(O)R⁷, S(O)₂OR⁷, S(O)R⁷, S(O)₂R⁷ andS(O)₂NR⁷R⁷; R^(5a) and R^(5b) are independently at each occurrenceselected from H, C₁-C₄-alkyl and halo; R⁶ is independently at eachoccurrence selected from: H, C₁-C₆-alkyl and C₁-C₆-haloalkyl; R⁷ andR^(6a) are independently at each occurrence selected from: H andC₁-C₆-alkyl; R⁸ is independently at each occurrence selected from: H,C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl; and wherein any ofthe abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, heteroaryl or phenyl groups is optionally substitutedwhere chemically allowable by from 1 to 4 groups independently selectedfrom oxo, C₁-C₆-alkyl, C₂-C₆-alkynyl, C₂-C₆-alkenyl, C₁-C₆-haloalkyl,OR^(a), NR^(a)R^(b), SR^(a), C(O)OR^(a), C(O)NR^(a)R^(a), halo, cyano,nitro, C(O)R^(a), S(O)₂OR^(a), S(O)₂R^(a) and S(O)₂NR^(a)R^(a); whereinR^(a) is independently at each occurrence selected from: H andC₁-C₆-alkyl; and R^(b) is independently at each occurrence selectedfrom: H, C₁-C₆-alkyl, C(O)C₁-C₆-alkyl and S(O)₂-C₁-C₆-alkyl.
 2. Thecompound according to claim 1, wherein R^(Z) is H, R^(X) is H, R^(Y) isCH₃, and R^(W) is OH.
 3. The compound according to claim 1, whereinR^(Z) is NMe₂, R^(X) is H, R^(Y) is H, and R^(W) is H.
 4. The compoundaccording to any one of claims 1 to 3, wherein L¹ is absent.
 5. Thecompound according to any one of claims 1 to 3, wherein L¹ isCR^(2a)R^(2b).
 6. The compound according to any one of claims 1 to 5,wherein L² is —NR^(3b)C(O)—.
 7. The compound according to any of claims1 to 6, wherein -(L⁵-L⁴-)_(n)-L³ is—(CR^(4a)R^(4b))_(o)-L⁴-(CR^(4c)R^(4d))_(p)—, wherein o is selected from3 to 10; p is selected from 1 to 3; wherein R^(4a) and R^(4b) are eachindependently at each occurrence selected from: H, C₁-C₆-alkyl,C₁-C₆-haloalkyl, OR⁶, and NR⁷R⁸; and R^(4c) and R^(4d) are eachindependently at each occurrence selected from: H and methyl.
 8. Thecompound according to claim 7, wherein -L⁴- is —NR^(3b)C(O)—
 9. Thecompound according to claim 7, wherein -L⁴- is absent.
 10. The compoundaccording to any of claims 1 to 9, wherein n, L¹, L², L³, L⁴ and L⁵ areselected such that length of the linker is from 8 to 14 atoms
 11. Acompound of any one of claims 1 to 10, wherein R^(1a), R^(1b) and R^(1c)are each substituted phenyl.
 12. A compound of any one of claims 1 to10, wherein R^(1a), R^(1b) and R^(1c) are each C₃ to C₈-cycloalkyl. 13.A compound of any one of claims 1 to 10, wherein R^(1a), R^(1b) andR^(1c) are each benzyl.
 14. A compound of any one of claims 1 to 10,wherein R^(1a) and R^(1b) are each unsubstituted phenyl and R^(1c) isindependently selected from: substituted phenyl, biphenyl, naphthyl, 5-,6-, 9- or 10-membered heteroaryl, C₃ to C₈-cycloalkyl, C₁-C₆-alkyl and4- to 8-membered heterocycloalkyl.
 15. A compound of any one of claims 1to 10, wherein R^(1a) and R^(1b) are each C₃ to C₈-cycloalkyl and R^(1c)is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9-or 10-membered heteroaryl, C₁-C₆-alkyl and 4- to 8-memberedheterocycloalkyl.
 16. A compound of any one of claims 1 to 10, whereinat least one of R^(1a), R^(1b) and R^(1c) is C₁-C₆-alkyl.
 17. A compoundof claim 16, wherein any of R^(1a), R^(1b) and R^(1c) that are notC₁-C₆-alkyl are phenyl.
 18. The compound according to claim 1, whereinthe cation of formula (I) is a formula selected from:


19. A compound according to any of claims 1 to 18, for medical use. 20.The compound according to any of claims 1 to 18, for use in thetreatment of cancer.
 21. A method for the treatment of cancer, whereinthe method comprises the administration of a therapeutically effectiveamount of a compound according to any one of claims 1 to
 18. 22. Apharmaceutical composition comprising the compound of claims 1 to 18 andone or more pharmaceutically acceptable excipients.